EP3463342A1 - Associations de modulateurs du récepteur des oestrogènes - Google Patents

Associations de modulateurs du récepteur des oestrogènes

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Publication number
EP3463342A1
EP3463342A1 EP17803574.7A EP17803574A EP3463342A1 EP 3463342 A1 EP3463342 A1 EP 3463342A1 EP 17803574 A EP17803574 A EP 17803574A EP 3463342 A1 EP3463342 A1 EP 3463342A1
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Prior art keywords
substituted
unsubstituted
nhc
heterocycloalkyl
alkyl
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EP17803574.7A
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German (de)
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EP3463342B1 (fr
EP3463342A4 (fr
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Richard J. Pietras
Michael E. Jung
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University of California
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University of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Breast cancer is the most common malignancyin women in NorthAmerica.Eachyear more than 210,000 new cases ofbreast cancer are diagnosed in the US (1-3).In the clinic, endocrine therapyis an important intervention for cancers that express estrogen receptor (ER), and it has proven to be one ofthe most effective treatment strategies for breast cancer (3,4).At diagnosis, about 70% ofbreast cancers contain estrogen receptors and depend on estrogen for growthand progression.Expression ofER in a tumor is predictive ofa clinical response to hormonal therapy.Suchobservations have led to current use ofantiestrogens (suchas fulvestrant, tamoxifen and its relatives, raloxifene, toremifene, lasofoxifene, etc.)and aromatase inhibitors in treating ER-positive breast cancer (2,3).Tamoxifen and its analogues are among the most highly prescribed drugs for initial estrogen-dependent breast cancer.However, theyare not without their drawbacks since theybind to the estrogen receptor in manyt
  • Estrogen modulates gene transcription in breast cancers throughits receptors using different signaling pathways (2,8)(see FIG.1).
  • the classical pathwayinvolves direct DNA binding of liganded receptor to estrogen response elements (EREs)in the promoter regions ofresponsive genes.
  • E2 estrogen response elements
  • ER estrogen receptor
  • ER ⁇ generally considered most important in tumor progression (5,6,9).
  • ER ⁇ has 6 major functional domains including an N-terminal transactivation domain, an adjacent DNA-binding domain and a C-terminal portion involved in hormone-binding, receptor dimerization and activity of a second transactivation region.
  • E2 binds ER to promote dimerization and phosphorylation ofthe receptor. This allows direct binding ofthe ligand-ER complexwithsteroid receptor coactivators (CoReg)and E2-responsive elements (ERE)in DNA, leading to changes in gene transcription that regulate growth, differentiation, apoptosis and angiogenesis.
  • CoReg the ligand-ER complexwithsteroid receptor coactivators
  • ERP E2-responsive elements
  • a subset ofER associate with extranuclear sites and interact there withmembrane growthfactor receptors (EGFR, HER2)and other signaling molecules (components ofthe ras-MAPK and PI3K/AKTpathways, Shc
  • ER often continues to playa major role in controlling growthofhormone-resistant cancers.
  • AI antiaromatase inhibitors
  • ER activation byalternate ligands local E2 production and development ofER hypersensitivityare especiallyproblematic (2,6).
  • ligand-independent activation ofER occurs in tumors overexpressing growthfactor receptors suchas HER2, withgrowthfactor receptors promoting ER phosphorylation even in the absence ofestrogen (5,9,11).Suchligand-independent mechanisms likelycontribute to resistance to AI’s as well as antiestrogens (12,13).
  • These nonclassical events are mediated byER or adaptor proteins that impact gene expression indirectlybyactivating growth-promoting kinase cascades to regulate transcription.
  • breast tumors significant evidence suggests that regulation ofboth proliferation and cell deathpathways occurs, in part, bythe action ofnonclassical kinase- mediated pathways (9,11,14-19).Better understanding and targeting ofthese complexsignaling pathways in
  • ER degradation limits hormone action.Ligand-induced down-regulation ofER is a pivotal step in halting E2 stimulation ofgrowth, and the ubiquitin–proteasome pathwayis the major system for selective degradation of such regulatory proteins (30). ER ⁇ was among the first ofthe nuclear receptors identified as substrates for this pathway(31-34).A common feature of proteasome-mediated protein degradation is covalent attachment ofubiquitin to lysine residues of proteins targeted for degradation followed byformation ofpolyubiquitin chains attached covalently to the protein.
  • Ubiquitinated ER ⁇ is recognized and degraded by the multisubunit protease complex, the 26S proteasome (35).ER is degraded in a hormone-dependent manner, withthis process contributing to regulation ofhormone action;and the proteasome inhibitor, MG132, is well known to promote invivo accumulation ofER and to blockligand-induced ER degradation (33).As noted above, the proteasome pathwayalso plays a critical role in interaction ofER withantagonists, suchas SERMs and fulvestrant (27, 34).
  • composition including a CDK4 inhibitor or a CDK6 inhibitor and a compound, or a pharmaceuticallyacceptable salt thereof, having the formula (I):
  • R 1 is independentlya hydrogen, halogen, -NR 2 R 3 , -CX a
  • R 2 is independentlya hydrogen
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 4 is independentlya hydrogen, halogen, -CX d
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independently hydrogen, halogen, -CX 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, - SO 4 H,
  • n is an integer from 0 to 5.
  • the symbols m1, m2, m3, m4, v1, v2, v3, and v4 are independently1 or 2.
  • the symbols n1, n2, n3, and n4 are independentlyan integer from 0 to 4.
  • the symbols X, X a , X b , X c and X d are independently–Cl, -Br, -I, or -F.
  • a kit including a CDK4 inhibitor or a CDK6 inhibitor, and a compound having the structure ofFormula (I)as disclosed herein, or pharmaceutically acceptable salt thereof.
  • a method oftreating a hyperproliferative disorder in a subject in need thereof including administering to the subject an effective amount of a composition as disclosed herein, or the compound and the CDK4 inhibitor or CDK6 inhibitor of a kit as disclosed herein.
  • a method ofinhibiting estrogen receptor activityin a subject in need thereof including administering to the subject an effective amount of a composition as disclosed herein, or the compound and the CDK4 inhibitor or CDK6 inhibitor of a kit as disclosed herein.
  • FIG.S. Interactions ofestrogen and growthfactor receptor signaling pathways in cancer cells.
  • FIG.S2.Antiestrogen JD140 elicits enhanced PARP cleavage in NSCLC cells.A549 cells were treated in 5% DCC-FBS phenol-red free RPMI1640 withvehicle control (C)or increasing concentrations ofJD140 at 0.01, 0.1 and 1 ⁇ M or 0.1 ⁇ M fulvestrant (F)for 4 hours. W estern Blots were performed using anti-cleaved-PARP antibody(Cell Signaling Technology). RPL13A is shown as loading control. The W estern blot is representative of3 independent experiments.
  • FIG.3.Estrogen receptor-alpha is down-regulated byantiestrogens.
  • FIG.S3.Tumor cell cycle regulation byCDK 4/6 and cyclin D The cell cycle clock machinery.G0, M, G1, S and G2 refer to quiescence, mitosis, first gap, DNA synthesis and 2nd gap phases ofthe cell cycle, respectively.
  • the restriction point (R-Point)is shown.Rb and Rb-p represent unphosphorylated and hyper-phosphorylated forms ofretinoblastoma (Rb)protein that regulates the cell cycle;modified from Lundberg & W einberg Eur JCancer.1999;35:1886).
  • FIGS.4A-4B.MCF-7 cells withacquired tamoxifen resistance show increased expression ofHER-1/EGFR and HER-2 receptors.
  • FIG.S4.Palbociclib in combination withletrozole blocks phosphorylation ofRb serine-780 in A549 cells.Cells were treated 24 hin phenol red-free RPMIwith1% DCC-FBS with vehicle control (CON), 1 nM estradiol-17 ⁇ (E2), 1 nM androstenedione (And), 10 nM testosterone (Tes), 10 ⁇ M letrozole (AI), 100 nM palbociclib (Plbo) or both Plbo + AI.
  • FIG.5. Specific binding of[3H]estradiol-17 ⁇ byMCF-7 parental breast cancer cells is suppressed byERD compound 15 (JD105).
  • Compounds S1-S14 in the present figure are comparative test compounds (different from individual compounds described herein)showing less inhibition than compound S15 in the present assay.
  • FIG.S5.Letrozole (AI)byblocking estrogen signaling reduces cyclin D1 expression in A549 NSCLC cells using W estern immunoblot methods.Cells were treated 24 hin phenol red-free RPMIwith1% DCC-FBS.Control (Con), estradiol-17 ⁇ (E2;1 nM), androstenedione (And;1 nM), testosterone (Tst;10 nM), letrozole (AI;10 ⁇ M)and palbociclib (Plbo;1 ⁇ M)were used in this experiment.GADPH is used as a loading control (20). [0029] FIG.6.ERD S15 reduces ER protein levels in MCF-7 breast tumor cells.
  • FIG.S6.Palbociclib and letrozole dosed as single agents and combined as a dual therapyinvitro in human NSCLC cells A549.Eachdrug elicits dose-dependent inhibition of NSCLC cell proliferation as compared to controls when administered for 72 hrs.However, treatment witha combination ofeither palbociclib (10-nM)/letrozole (10- ⁇ M)[10P/10L]or palbociclib (100nM)/ letrozole (10 ⁇ M)[100P/10L]for 72 hinvitro elicits enhanced inhibition ofcell proliferation ofNSCLC cells, indicating potential synergyin dual therapy.This finding corresponds to the synergistic interaction ofpalbociclib withantiestrogen agents that was previouslyreported in hormone receptor-positive human breast cancer cells under invitro conditions [19,20].
  • FIG.S7.SERD 128 down-regulates cyclin D1 in MCF-7 breast cancer cells.W estern immunoblot of cyclin D1 after treating MCF-7 cells 24 hrs with 10% FBS and 1 ⁇ M and 10 ⁇ M doses ofJD105, JD128 and JD140.Refer to FIG.S4 methods and previous reports (20).
  • FIG.8.Novel antiestrogen JD140 elicits significant antiproliferative effects in human non-small cell lung cancer cells A549 as compared withthe activityoffulvestrant.
  • FIG.S8.SERD compounds in combination withthe CDK 4/6 inhibitor palbociclib blocks NSCLC cell proliferation invitro.In panel (a), NSCLC cells were treated with palbociclib alone at 1 ⁇ M.In panel (b), tumor NSCLC cells were treated withSERD compounds 103,140 or 160 alone at a dose of10 ⁇ M.In panel (c), NSCLC cells are treated witha combination ofpalbociclib at 1 ⁇ M withSERD compounds indicated in the figure at 10 ⁇ M.See methods below.Mean cell proliferation values +SE are shown as % controls.
  • FIG.9 Activation of estrogen receptor (ER) by estradiol-17 ⁇ or by growth factor receptor signaling promotes gene transcription for tumor cell proliferation and inhibition of apoptosis.Disruption byselective estrogen receptor downregulators ofcritical steps in these pathways includes downstream actions suchas modulation ofcyclin D expression in the control ofthe cell cycle and proliferation and regulation ofapoptosis.
  • ER estrogen receptor
  • FIG.10 S128 in combination withpalbociclib (Pb), a CDK4/CDK6 inhibitor, blocks endocrine-resistant breast cancer (BC)cell proliferation invitro.
  • W here substituent groups are specified bytheir conventional chemical formulae, written from left to right, theyequallyencompass the chemicallyidentical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl byitselfor as part ofanother substituent, means, unless otherwise stated, a straight (i.e., unbranched)or branched non-cyclic carbon chain (or carbon), or combination thereof, whichmaybe fullysaturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number ofcarbon atoms designated (i.e., C 1 -C 10 means one to ten carbons).
  • examples ofsaturated hydrocarbon radicals include, but are not limited to, groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,
  • cyclohexyl (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder ofthe molecule via an oxygen linker (-O-).
  • An alkyl moiety maybe an alkenyl moiety.
  • An alkyl moiety maybe an alkynyl moiety.
  • alkyl moiety maybe fullysaturated.
  • alkylene byitselfor as part ofanother substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited
  • alkyl (or alkylene)group will have from 1 to 24 carbon atoms, withthose groups having 10 or fewer carbon atoms being preferred in the present invention.
  • A“lower alkyl”or“lower alkylene” is a shorter chain alkyl or alkylene group, generallyhaving eight or fewer carbon atoms.
  • alkenylene byitselfor as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl byitselfor in combination withanother term, means, unless otherwise stated, a stable non-cyclic straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g.O, N, P, Si, and S)and wherein the nitrogen and sulfur atoms mayoptionallybe oxidized, and the nitrogen heteroatom mayoptionallybe quaternized.
  • the heteroatom(s)(e.g.O, N, P, S, and Si) maybe placed at any interior position ofthe heteroalkyl group or at the position at whichthe alkyl group is attached to the remainder ofthe molecule.
  • examples include, but are not limited
  • heteroalkylene means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupyeither or bothofthe chain termini (e.g.,alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).Still further, for alkylene and heteroalkylene linking groups, no orientation ofthe linking group is implied bythe direction in whichthe formula ofthe linking group is written.For example, the formula -C(O) 2 R'- represents both-C(O) 2 R'- and -R'C(O) 2 -.As described above, heteroalkyl groups, as
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, suchas -NR'R'or the like.
  • a heteroatom can occupythe position at whichthe heterocycle is attached to the remainder ofthe molecule.
  • Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohe
  • halo or“halogen,”bythemselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl a polyunsaturated, aromatic, hydrocarbon substituent, whichcan be a single ring or multiple rings (preferablyfrom 1 to 3 rings)that are fused together (i.e., a fused ring aryl)or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one ofthe fused rings is an aryl ring.
  • the term “heteroaryl” refer to aryl groups (or rings)that contain at least one heteroatom suchas N, O, or S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s)are optionallyquaternized.
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein
  • aryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.
  • An“arylene”and a“heteroarylene,”alone or as part ofanother substituent mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • Non-limiting examples ofaryl and heteroaryl groups include pyridinyl,
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring
  • heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl mayeachindependentlybe unsubstituted or substituted withone or more ofthe substituents described herein. [0051]
  • the term“oxo,”as used herein, means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moietyhaving the formula -S(O 2 )-R', where R'is a substituted or unsubstituted alkyl group as defined above.R'mayhave a specified number ofcarbons (e.g.,“C 1 -C 4 alkylsulfonyl”).
  • -NR'C (O)NR'NR''R'', -CN, -NO 2 , in a number ranging from zero to (2m'+1), where m'is the total number ofcarbon atoms in suchradical.R, R', R', R'', and R''eachpreferably
  • unsubstituted aryl e.g., aryl substituted with1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxygroups, or arylalkyl groups.
  • W hen a compound ofthe invention includes more than one R group, for example, eachofthe R groups is independentlyselected as are eachR', R', R'', and R''group when more than one of these groups is present.
  • W hen R'and R' are attached to the same nitrogen atom, theycan be combined withthe nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, suchas haloalkyl (e.g., -CF 3 and -CH 2 CF 3 )and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • -NR'C (O)NR'NR''R'', -CN, -NO 2 , -R', -N 3 , -CH(Ph) 2 , fluoro(C 1 -C 4 )alkoxy, and fluoro(C 1 - C 4 )alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system;and where R', R', R'', and R''are preferablyindependentlyselected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • a compound ofthe invention includes more than one R group, for example, eachofthe R groups is independently selected as are eachR', R', R'', and R''groups when more than one ofthese groups is present.
  • Two or more substituents mayoptionallybe joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • ring-forming substituents are typically, thoughnot necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members ofthe base structure.
  • two ring-forming substituents attached to adjacent members ofa cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member ofthe base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring- forming substituents are attached to non-adjacent members ofthe base structure.
  • Two ofthe substituents on adjacent atoms ofthe aryl or heteroaryl ring mayoptionally form a ring ofthe formula -T-C(O)-(CRR') q -U-, wherein Tand U are
  • two ofthe substituents on adjacent atoms ofthe aryl or heteroaryl ring may optionallybe replaced with a substituent ofthe formula -A-(CH 2 ) r -B-, wherein A and B are independently-CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer offrom 1 to 4.
  • One ofthe single bonds ofthe new ring so formed mayoptionallybe replaced witha double bond.
  • two ofthe substituents on adjacent atoms ofthe aryl or heteroaryl ring mayoptionallybe replaced witha substituent ofthe
  • R, R', R', and R'' are preferablyindependentlyselected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heterocycloalkyl unsubstituted aryl, unsubstituted heteroaryl, and (b)alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,
  • A“size-limited substituent”or“size-limited substituent group,”as used herein, means a group selected from all ofthe substituents described above for a“substituent group,”wherein eachsubstituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, eachsubstituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, eachsubstituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted
  • A“lower substituent”or“lower substituent group,”as used herein, means a group selected from all ofthe substituents described above for a“substituent group,”wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and eachsubstituted or
  • eachsubstituted group described in the compounds herein is substituted withat least one substituent group.
  • each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted withat least one substituent group.
  • at least one or all ofthese groups are substituted withat least one size-limited substituent group.
  • at least one or all ofthese groups are substituted withat least one lower substituent group.
  • eachsubstituted or unsubstituted alkyl maybe a substituted or unsubstituted C 1 -C 20 alkyl
  • eachsubstituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • eachsubstituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • eachsubstituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • eachsubstituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • eachsubstituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • eachsubstituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • eachsubstituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • eachsubstituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • eachsubstituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • salts ofthe active compounds that are prepared withrelativelynontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form ofsuchcompounds witha sufficient amount ofthe desired base, either neat or in a suitable inert solvent.
  • examples ofpharmaceuticallyacceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained bycontacting the neutral form ofsuchcompounds witha sufficient amount ofthe desired acid, either neat or in a suitable inert solvent.
  • pharmaceuticallyacceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • the compounds ofthe present invention mayexist as salts, suchas with pharmaceuticallyacceptable acids.
  • the present invention includes suchsalts.
  • Such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts withamino acids suchas glutamic acid.
  • These salts maybe prepared bymethods known to those skilled in the art.
  • the neutral forms ofthe compounds are preferablyregenerated bycontacting the salt witha base or acid and isolating the parent compound in the conventional manner.
  • the parent form ofthe compound differs from the various salt forms in certain physical properties, suchas solubilityin polar solvents.
  • agents e.g.compounds, drugs, therapeutic agents
  • Prodrugs ofthe compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents).
  • prodrugs can be converted to agents (e.g.
  • Prodrugs described herein include compounds that readilyundergo chemical changes under select physiological conditions to provide agents (e.g.compounds, drugs, therapeutic agents)to a biological system (e.g.in a subject, in a cancer cell, in the extracellular space near a cancer cell).
  • Certain compounds ofthe present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope ofthe present invention.Certain compounds ofthe present invention mayexist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplated bythe present invention and are intended to be within the scope ofthe present invention.
  • salt refers to acid or base salts ofthe compounds used in the methods ofthe present invention.
  • Acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like)salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternaryammonium (methyl iodide, ethyl iodide, and the like)salts.
  • Certain compounds ofthe present invention possess asymmetric carbon atoms (optical or chiral centers)or double bonds;the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that maybe defined, in terms ofabsolute
  • the term“isomers” refers to compounds having the same number and kind ofatoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration ofthe atoms.
  • the term“tautomer,”as used herein, refers to one oftwo or more structural isomers whichexist in equilibrium and whichare readilyconverted from one isomeric form to another.
  • certain compounds ofthis invention may exist in tautomeric forms, all suchtautomeric forms ofthe compounds being within the scope of the invention.
  • structures depicted herein are also meant to include all stereochemical forms ofthe structure;i.e., the R and S configurations for eachasymmetric center.Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures ofthe present compounds are within the scope ofthe invention.
  • structures depicted herein are also meant to include compounds whichdiffer onlyin the presence ofone or more isotopicallyenriched atoms.For example, compounds having the present structures except for the replacement ofa hydrogen bya deuterium or tritium, or the replacement ofa carbon by 13 C- or 14 C-enriched carbon are within the scope ofthis invention.
  • the compounds ofthe present invention may also contain unnatural proportions of atomic isotopes at one or more ofthe atoms that constitute suchcompounds.
  • the compounds maybe radiolabeled withradioactive isotopes, suchas for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations ofthe compounds ofthe present invention, whether radioactive or not, are encompassed within the scope ofthe present invention.
  • the symbol“ ” denotes the point ofattachment ofa chemical moietyto the remainder ofa molecule or chemical formula.
  • the terms“treating”or“treatment” refers to anyindicia ofsuccess in the treatment or amelioration ofan injury, disease, pathologyor condition, including anyobjective or subjective parameter suchas abatement;remission;diminishing ofsymptoms or making the injury, pathologyor condition more tolerable to the patient;slowing in the rate ofdegeneration or decline;making the final point ofdegeneration less debilitating;improving a patient’s physical or mental well-being.
  • the treatment or amelioration ofsymptoms can be based on objective or subjective parameters;including the results ofa physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • certain methods herein treat diseases associated withestrogen receptor activity.Certain methods described herein maytreat diseases associated withestrogen receptor activity(e.g., breast cancer, lung cancer, a gynecological cancer, ovarian cancer, endometrial cancer, or prostate cancer, lymphangioleiomyomatosis (LAM)
  • Certain methods described herein maytreat diseases associated withhyperproliferation (e.g., of cells).For example, certain methods herein treat cancer.For example certain methods herein treat cancer bydecreasing a symptom ofcancer.Symptoms ofcancer would be known or may be determined bya person ofordinaryskill in the art. The term “treating” and conjugations thereof, include prevention ofinjury, pathology, condition, or disease. [0082] An“effective amount”is an amount sufficient to accomplisha stated purpose (e.g.
  • an“effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms ofa disease, whichcould also be referred to as a“therapeuticallyeffective amount.”
  • A“prophylacticallyeffective amount”ofa drug or prodrug is an amount ofa drug or prodrug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence)ofan injury, disease, pathologyor condition, or reducing the likelihood ofthe onset (or reoccurrence)ofan injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarilyoccur byadministration of
  • the term“associated”or“associated with”in the context of a substance or substance activityor function associated witha disease e.g.hyperproliferative disease, cancer
  • a disease associated withestrogen receptor activity maybe treated withan agent (e.g.compound as described herein)effective for decreasing the level ofestrogen receptor activity.
  • Control or“control experiment”or“standard control”is used in accordance withits plain ordinary meaning and refers to an experiment in whichthe subjects or reagents ofthe experiment are treated as in a parallel experiment except for omission ofa procedure, reagent, or variable ofthe experiment.In some instances, the control is used as a standard ofcomparison in evaluating experimental effects.
  • Contacting is used in accordance withits plain ordinary meaning and refers to the process ofallowing at least two distinct species (e.g.chemical compounds including
  • biomolecules, or cells to become sufficientlyproximal to react, interact or physicallytouch.
  • the resulting reaction product can be produced directlyfrom a reaction between the added reagents or from an intermediate from one or more ofthe added reagents whichcan be produced in the reaction mixture.
  • the term“contacting” mayinclude allowing two species to react, interact, or physicallytouch, wherein the two species maybe a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact witha protein or enzyme.
  • inhibition means negativelyaffecting (e.g.decreasing)the level ofactivityor function ofthe protein relative to the level ofactivityor function ofthe protein in the absence ofthe inhibitor.
  • inhibition refers to reduction ofa disease or symptoms ofdisease.Thus, inhibition mayinclude, at least in part, partiallyor totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating,
  • the term“activation”,“activate”,“activating”and the like in reference to a protein-activator (e.g.agonist)interaction means positivelyaffecting (e.g.
  • activation mayinclude, at least in part, partiallyor totallyincreasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease.
  • activation mayinclude, at least in part, partiallyor totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activityor the amount ofa protein.
  • modulator refers to a composition that increases or decreases the level ofa target molecule or the function ofa target molecule.
  • a modulator is an anti- cancer agent.
  • a modulator is an estrogen receptor antagonist.
  • a modulator is a hormone receptor antagonist.
  • a modulator is an estrogen receptor inhibitor.
  • a modulator is an estrogen receptor covalent modifier.
  • An“additional agent”or“further agent”, as used herein, refer to a compound for use in conjuction withthe compounds provided herein (the compunds ofFormula Iand embodiments thereof).
  • An additional agent or further agent maybe an anti-cancer agent.
  • the additional agent or further agent is an agent for treating a hyperproliferative disorder.
  • the further agent is a chemotherapeutic.
  • the further agent is an agent for treating breast cancer.
  • the further agent is an agent for treating lung cancer.
  • the further agent is an agent for treating a gynecological cancer.
  • the further agent is an agent for treating ovarian cancer.
  • the further agent is an agent for treating endometrial cancer.
  • the further agent is an agent for treating prostate cancer.
  • the further agent is an agent for treating lymphangioleiomyomatosis.
  • the further agent is an agent for inhibiting estrogen receptor activity.
  • the additional agent or further agent is an agent for treating a hyperproliferative disorder.
  • the further agent is an aromatase inhibitor.
  • the further agent is a HER-2 inhibitor.
  • the further agent is Herceptin.
  • the further agent is fulvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, or testolactone.
  • the further agent is tamoxifen.
  • the further agent is an EGFR inhibitor (e.g.gefitinib (IressaTM), erlotinib (Tarceva TM), cetuximab (ErbituxTM), lapatinib (TYKERBTM), panitumumab (VECTIBIXTM), vandet
  • EGFR inhibitor e.g.gefit
  • the further agent is a mammalian target ofrapamycin (mTOR) inhibitor (suchas everolimus)for use in treating cancer (e.g.in breast and NSCLC tumors); HER2-targeted therapeutics (suchas trastuzumab, lapatinib, trastuzumab- emtansine)for use in treating cancer (e.g.ER-positive breast cancers withoverexpression ofHER-2 receptors);HER3- targeted agents (e.g.pertuzumab);EGFR-targeted therapeutics (suchas erlotinib, gefitinib, afitinib)for treating cancer (e.g.NSCLC expressing mutant EGFR or having EGFR-positivity); tamoxifen or aromatase inhibitors
  • mTOR mammalian target ofrapamycin
  • HER2-targeted therapeutics suchas trastuzumab, lapatinib, trastuzumab- emtansine
  • Anti-cancer agent or“anti-cancer drug” is used in accordance withits plain ordinary meaning and refers to a composition (e.g.compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the abilityto inhibit the growthor proliferation ofcells.
  • an anti-cancer agent is a chemotherapeutic.
  • an anti- cancer agent is an agent approved bythe FDA or similar regulatoryagencyofa countryother than the USA, for treating cancer.
  • anti-androgens e.g., Casodex, Flutamide, MDV3100, or ARN-509
  • MEK e.g.MEK1, MEK2, or MEK1 and MEK2
  • Inhibitors e.g.XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, AR
  • cyclophosphamide ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine,
  • cyclophosphamide chlorambucil, meiphalan
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, semustine, streptozocin
  • triazenes decarbazine
  • anti-metabolites e.g.,5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant
  • fluorodaunorunicin hydrochloride gadolinium texaphyrin;gallium nitrate;gelatinase inhibitors; gemcitabine;glutathione inhibitors;hepsulfam;immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor;interferon agonists;interferons;interleukins;letrozole;leukemia inhibiting factor;leukocyte alpha interferon;leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors;matrixmetalloproteinase inhibitors;MIFinhibitor;mifepristone;
  • mismatched double stranded RNA mismatched double stranded RNA;monoclonal antibody,;mycobacterial cell wall extract;nitric oxide modulators;oxaliplatin;panomifene;pentrozole;phosphatase inhibitors;plasminogen activator inhibitor;platinum complex;platinum compounds;prednisone;proteasome inhibitors; protein A-based immune modulator;protein kinase C inhibitor;protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors;ras farnesyl protein transferase inhibitors; ras inhibitors;ras-GAP inhibitor;ribozymes;signal transduction inhibitors;signal transduction modulators;single chain antigen-binding protein;stem cell inhibitor;stem-cell division inhibitors;stromelysin inhibitors;synthetic glycosaminoglycans;tamoxifen methiodide;
  • telomerase inhibitors e.g., thyroid stimulating hormone;translation inhibitors;tyrosine kinase inhibitors;urokinase receptor antagonists;steroids (e.g.,dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH)suchas goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate,
  • GnRH gonadotropin-releasing hormone agonists
  • progestins e.g., hydroxypro
  • fluoxymesterone antiandrogen (e.g., flutamide), immunostimulants (e.g.,Bacillus Calmette- Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGFmonoclonal antibodies), immunotoxins (e.g.,anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g.,anti- CD20 monoclonal antibodyconjugated to 111 In, 90 Y, or 131 I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastat
  • duocarmycin analogs duocarmycin analogs, enediynes (suchas neocarzinostatin and calicheamicins), leptomycin derivatives, maytansinoids and maytansinoid analogs (e.g.mertansine), methotrexate, mitomycin C, taxoids, vinca alkaloids (suchas vinblastine and vincristine), epothilones (e.g.epothilone B), fluvestrant, camptothecin and its clinical analogs topotecan and irinotecan, SERMS (e.g., clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene,
  • SERMS e.g., clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremif
  • “Chemotherapeutic”or“chemotherapeutic agent” is used in accordance withits plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the abilityto inhibit the growthor proliferation ofcells.
  • “Patient”or“subject in need thereof”or“subject” refers to a living organism suffering from or prone to a disease or condition that can be treated byadministration ofa compound or pharmaceutical composition or bya method, as provided herein.Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.In some embodiments, a patient is human. In some embodiments, a subject is human. [0093] “Disease”or“condition”refer to a state ofbeing or healthstatus ofa patient or subject capable ofbeing treated witha compound, pharmaceutical composition, or method provided herein.In some embodiments, the disease is a disease having the symptom ofcell
  • the disease is a disease having the symptom ofan aberrant level ofestrogen receptor activity.
  • the disease is a cancer.
  • “cancer” refers to human cancers and carcinomas, sarcomas,
  • adenocarcinomas, lymphomas, leukemias, etc. including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • the disease is breast cancer.
  • the disease is hormone sensitive breast cancer.
  • the disease is hormone refractory (insensitive)breast cancer.
  • the disease is ER positive breast cancer.
  • the disease is ER negative breast cancer.
  • Exemplarycancers that maybe treated with a compound or method provided herein include cancer ofthe prostate, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer.
  • Additional examples mayinclude, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primarythrombocytosis, primary macroglobulinemia, primarybrain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinarybladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblasto
  • leukemia refers broadlyto progressive, malignant diseases ofthe blood- forming organs and is generallycharacterized bya distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.Leukemia is generallyclinically classified on the basis of(1)the duration and character ofthe disease-acute or chronic;(2)the type ofcell involved;myeloid (myelogenous), lymphoid (lymphogenous), or monocytic;and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplaryleukemias that maybe treated witha compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic le
  • hemocytoblastic leukemia histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,
  • sarcoma generally refers to a tumor whichis made up of a substance like the embryonic connective tissue and is generallycomposed ofcloselypacked cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that maybe treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that maybe treated witha compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passeymelanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growthmade up ofepithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • Exemplarycarcinomas that maybe treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullarythyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,
  • signaling pathway refers to a series ofinteractions between cellular and optionallyextra-cellular components (e.g.proteins, nucleic acids, small molecules, ions, lipids)that conveys a change in one component to one or more other components, whichin turn mayconveya change to additional components, whichis optionallypropagated to other signaling pathwaycomponents.
  • optionallyextra-cellular components e.g.proteins, nucleic acids, small molecules, ions, lipids
  • aberrant refers to different from normal.W hen used to describe enzymatic activity, aberrant refers to activitythat is greater or less than a normal control or the average ofnormal non-diseased control samples.Aberrant activitymayrefer to an amount ofactivitythat results in a disease, wherein returning the aberrant activityto a normal or non- disease-associated amount (e.g.byadministering a compound or using a method as described herein), results in reduction ofthe disease or one or more disease symptoms.
  • nucleic acid or“oligonucleotide”or“polynucleotide”or grammatical equivalents used herein means at least two nucleotides covalentlylinked together.
  • Oligonucleotides are typicallyfrom about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length.
  • Nucleic acids and polynucleotides are a polymers ofanylength, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc.
  • Nucleic acids containing one or more carbocyclic sugars are also included within one definition ofnucleic acids.
  • a particular nucleic acid sequence also encompasses“splice variants.”
  • a particular protein encoded bya nucleic acid encompasses anyprotein encoded bya splice variant ofthat nucleic acid.“Splice variants,”as the name suggests, are products ofalternative splicing ofa gene.After transcription, an initial nucleic acid transcript maybe spliced suchthat different (alternate)nucleic acid splice products encode different polypeptides.
  • Mechanisms for the production ofsplice variants vary, but include alternate splicing ofexons.Alternate polypeptides derived from the same nucleic acid byread-throughtranscription are also encompassed bythis definition.Anyproducts ofa splicing reaction, including recombinant forms ofthe splice products, are included in this definition.
  • a nucleic acid is“operablylinked”when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretoryleader is operablylinked to DNA for a polypeptide ifit is expressed as a preprotein that participates in the secretion ofthe polypeptide;
  • a promoter or enhancer is operablylinked to a coding sequence ifit affects the transcription ofthe sequence; or
  • a ribosome binding site is operablylinked to a coding sequence ifit is positioned so as to facilitate translation.
  • “operablylinked” means that the DNA sequences being linked are near eachother, and, in the case ofa secretoryleader, contiguous and in reading phase.However, enhancers do not have to be contiguous.Linking is accomplished byligation at convenient restriction sites.Ifsuchsites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance withconventional practice.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage ofamino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% ,94%, 95%, 96%, 97%, 98%, 99% or higher identityover a specified region when compared and aligned for maximum correspondence over a comparison window or designated region)as measured using a BLASTor BLAST2.0 sequence comparison algorithms withdefault parameters described below, or byman
  • identity forms over a region that is at least about 10 amino acids or 20 nucleotides in length, or more preferablyover a region that is 10-50 amino acids or 20-50 nucleotides in length.
  • percent (%)amino acid sequence identity is defined as the percentage ofamino acids in a candidate sequence that are identical to the amino acids in a reference sequence, after aligning the sequences and introducing gaps, ifnecessary, to achieve the maximum percent sequence identity.Alignment for purposes ofdetermining percent sequence identitycan be achieved in various ways that are within the skill in the art, for instance, using publiclyavailable computer software suchas BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software.Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-lengthofthe sequences being compared can be determined byknown methods.
  • sequence comparisons typicallyone sequence acts as a reference sequence, to whichtest sequences are compared.W hen using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.
  • A“comparison window”, as used herein, includes reference to a segment ofanyone of the number ofcontiguous positions selected from the group consisting offrom 10 to 600, usually about 50 to about 200, more usuallyabout 100 to about 150 in which a sequence maybe compared to a reference sequence ofthe same number ofcontiguous positions after the two sequences are optimallyaligned.
  • Methods ofalignment ofsequences for comparison are well- known in the art.
  • Optimal alignment ofsequences for comparison can be conducted, e.g., bythe local homologyalgorithm ofSmith& W aterman, Adv.Appl.Math.2:482 (1981), bythe homologyalignment algorithm ofNeedleman & W unsch, J.Mol.Biol.48:443 (1970), bythe searchfor similaritymethod ofPearson & Lipman, Proc.Nat’l.Acad.Sci.USA 85:2444 (1988), bycomputerized implementations
  • phrase“selectively(or specifically)hybridizes to” refers to the binding, duplexing, or hybridizing of a molecule onlyto a particular nucleotide sequence witha higher affinity, e.g., under more stringent conditions, than to other nucleotide sequences (e.g., total cellular or library DNA or RNA).
  • stringent hybridization conditions refers to conditions under whicha probe will hybridize to its target subsequence, typicallyin a complexmixture ofnucleic acids, but to no other sequences.Stringent conditions are sequence-dependent and will be different in different circumstances.Longer sequences hybridize specificallyat higher temperatures.An extensive guide to the hybridization ofnucleic acids is found in Tijssen, Techniques in
  • stringent conditions are selected to be about 5-10°C lower than the thermal melting point (T m )for the specific sequence at a defined ionic strengthpH.
  • T m is the temperature (under defined ionic strength, pH, and nucleic concentration)at which50% ofthe probes complementaryto the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T m , 50% ofthe probes are occupied at equilibrium).
  • Stringent conditions may also be achieved withthe addition ofdestabilizing agents suchas formamide.
  • a positive signal is at least two times background, preferably10 times background hybridization.
  • Exemplarystringent hybridization conditions can be as following: 50% formamide, 5xSSC, and 1% SDS, incubating at 42°C, or, 5xSSC, 1%
  • nucleic acids that do not hybridize to eachother under stringent conditions are still substantiallyidentical if the polypeptides whichtheyencode are substantiallyidentical.This occurs, for example, when a copyofa nucleic acid is created using the maximum codon degeneracypermitted bythe genetic code.In suchcases, the nucleic acids typicallyhybridize under moderatelystringent hybridization conditions.
  • Exemplary moderatelystringent hybridization conditions” include a hybridization in a buffer of40% formamide, 1 M NaCl, 1% SDS at 37°C, and a washin 1X SSC at 45°C.A positive hybridization is at least twice background.
  • substitution ofone amino acid residue for another within the same class or group is referred to herein as a“conservative”substitution.
  • Conservative amino acid substitutions can frequentlybe made in a protein without significantlyaltering the conformation or function ofthe protein.
  • substitution ofone amino acid residue for another from a different class or group is referred to herein as a“non-conservative”substitution.
  • non-conservative amino acid substitutions tend to modifyconformation and function ofa protein.
  • the conservative amino acid substitution comprises substituting anyofglycine (G), alanine (A), isoleucine (I), valine (V), and leucine (L)for anyother ofthese aliphatic amino acids;serine (S)for threonine (T)and vice versa;aspartic acid (D)for glutamic acid (E)and vice versa;glutamine (Q)for asparagine (N)and vice versa;lysine (K)for arginine (R)and vice versa;phenylalanine (F), tyrosine (Y)and tryptophan (W )for anyother ofthese aromatic amino acids;and methionine (M)for cysteine (C)and vice versa.Other substitutions can also be considered conservative, depending on the environment ofthe particular amino acid and its role in the three- dimensional structure ofthe protein.For example, glycine (G), glycine (G), isoleucine (I), valine (V), and le
  • Polypeptide,”“peptide,”and“protein” are used herein interchangeablyand mean any peptide-linked chain ofamino acids, regardless oflengthor post-translational modification.As noted below, the polypeptides described herein can be, e.g., wild-type proteins, biologically- active fragments ofthe wild-type proteins, or variants ofthe wild- type proteins or fragments.
  • Variants in accordance withthe disclosure, can contain amino acid substitutions, deletions, or insertions. The substitutions can be conservative or non-conservative.
  • the proteins can be isolated.
  • the term“purified”or“isolated”as applied to anyofthe proteins described herein refers to a polypeptide that has been separated or purified from components (e.g., proteins or other naturally-occurring biological or organic molecules)whichnaturallyaccompanyit, e.g., other proteins, lipids, and nucleic acid in a cell expressing the proteins.
  • a polypeptide is purified when it constitutes at least 60 (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99)%, byweight, ofthe total protein in a sample.
  • an amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue.
  • a selected residue in a selected protein corresponds to Cys784 ofhuman androgen receptor when the selected residue occupies the same essential spatial or other structural relationship as Cys 784 in human androgen receptor.
  • the position in the aligned selected protein aligning withCys784 is said to correspond to Cys784.
  • a three dimensional structural alignment can also be used, e.g., where the structure ofthe selected protein is aligned for maximum correspondence withthe human androgen receptor protein and the overall structures compared.
  • an amino acid that occupies the same essential position as Cys784 in the structural model is said to correspond to the Cys784 residue.
  • “Pharmaceuticallyacceptable excipient”and“pharmaceuticallyacceptable carrier” refer to a substance that aids the administration ofan active agent to and absorption bya subject and can be included in a compositions disclosed herein without causing a significant adverse toxicological effect on the patient.
  • pharmaceuticallyacceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (suchas Ringer's solution), alcohols, oils, gelatins, carbohydrates suchas lactose, amylose or starch, fattyacid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.Suchpreparations can be sterilized and, ifdesired, mixed withauxiliaryagents such as lubricants, preservatives, stabilizers, wetting agents, and the like.
  • preparation is intended to include the formulation ofthe active compound withencapsulating material as a carrier providing a capsule in whichthe active component with or without other carriers, is surrounded by a carrier, whichis thus in association withit.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation ofa slow- release device, e.g.,a mini-osmotic pump, to a subject.
  • administering is byanyroute, including parenteral and transmucosal (e.g.,buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral and transmucosal e.g.,buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal.
  • Parenteral and transmucosal e.g.,buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal.
  • Parenteral and transmucosal e.g
  • the compound ofthe invention can be administered alone or can be coadministered to the patient.Coadministration is meant to include simultaneous or sequential administration ofthe compound individuallyor in combination (more than one compound or agent).Thus, the preparations can also be combined, when desired, withother active substances (e.g.to reduce metabolic degradation, to increase degradation ofa prodrug and release ofthe drug, detectable agent).
  • the compositions ofthe present invention can be delivered bytransdermally, bya topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion bythe patient.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible
  • compositions ofthe present invention can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection ofdrug-containing microspheres, whichslowlyrelease subcutaneously(see Rao, J.
  • the formulations ofthe compositions ofthe present invention can be delivered bythe use ofliposomes whichfuse with the cellular membrane or are endocytosed, i.e.,byemploying receptor ligands attached to the liposome, that bind to surface membrane protein receptors ofthe cell resulting in endocytosis.
  • compositions ofthe present invention can focus the delivery ofthe compositions ofthe present invention into the target cells in vivo.
  • the compositions ofthe present invention can also be delivered as nanoparticles.
  • compositions provided bythe present invention include compositions wherein the active ingredient (e.g.compounds described herein, including embodiments or examples)is contained in a therapeuticallyeffective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeuticallyeffective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia,on the condition being treated.W hen administered in methods to treat a disease, suchcompositions will contain an amount ofactive ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression ofdisease symptoms (e.g.
  • the dosage and frequency(single or multiple doses)administered to a mammal can varydepending upon a varietyoffactors, for example, whether the mammal suffers from another disease, and its route ofadministration;size, age, sex, health, bodyweight, bodymass index, and diet ofthe recipient;nature and extent ofsymptoms ofthe disease being treated (e.g.symptoms ofcancer), kind ofconcurrent treatment, complications from the disease being treated or other health-related problems.Other therapeutic regimens or agents can be used in conjunction with the methods and compounds ofApplicants'invention.Adjustment and manipulation of established dosages (e.g., frequencyand duration)are well within the abilityofthose skilled in the art.
  • the therapeuticallyeffective amount can be initiallydetermined from cell culture assays.Target concentrations will be those concentrations ofactive compound(s)that are capable ofachieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeuticallyeffective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted bymonitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above.Adjusting the dose to achieve maximal efficacyin humans based on the methods described above and other methods is well within the capabilities ofthe ordinarilyskilled artisan.
  • Dosages maybe varied depending upon the requirements ofthe patient and the compound being employed. The dose administered to a patient, in the context ofthe present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size ofthe dose also will be determined bythe existence, nature, and extent ofanyadverse side-effects.Determination ofthe proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated withsmaller dosages whichare less than the optimum dose ofthe compound.Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances is reached. [0123] Dosage amounts and intervals can be adjusted individuallyto provide levels ofthe administered compound effective for the particular clinical indication being treated.This will provide a therapeutic regimen that is commensurate withthe severityofthe individual's disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicityand yet is effective to treat the clinical symptoms demonstrated bythe particular patient. This planning should involve the careful choice ofactive compound byconsidering factors suchas compound potency, relative bioavailability, patient bodyweight, presence and severityofadverse side effects, preferred mode ofadministration and the toxicityprofile ofthe selected agent.
  • the compounds described herein can be used in combination withone another, with other active agents known to be useful in treating cancer, or withadjunctive agents that maynot be effective alone, but maycontribute to the efficacyofthe active agent.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours ofa second active agent.Co-administration includes administering two active agents simultaneously, approximatelysimultaneously(e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeachother), or sequentiallyin anyorder. In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical composition including bothactive agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents maybe linked or conjugated to one another. In some embodiments, the compounds described herein maybe combined withtreatments for cancer suchas radiation or surgery.
  • A“drug-resistant estrogen receptor” is a modified (relative to wildtype)estrogen receptor that is inhibited less effectivelybythe drug than a wildtype estrogen receptor.
  • A“drug- resistant human estrogen receptor” is a modified (relative to wildtype)human estrogen receptor that is inhibited less effectivelybythe drug than a wildtype human estrogen receptor.
  • A“drug-resistant cancer” is a cancer that is inhibited less effectivelybythe drug than a non-drug resistant cancer.
  • An“antiestrogen-resistant cancer” is a cancer that is inhibited less effectivelybythe antiestrogen than a non-antiestrogren resistant cancer.
  • An“endocrine therapeutic-resistant cancer” is a cancer that is inhibited less effectivelybythe endocrine therapeutic than a non-endocrine therapeutic resistant cancer.
  • antiestrogen refers to a compound that binds estrogen receptor without one or more ofthe estrogen receptor activities associated withthe binding ofestrogen to the estrogen receptor.
  • an antiestrogen is a compound that inhibits one or more effects of estrogen (e.g., on ER, on a cell, on a tissue, or on an organism).
  • an antiestrogen include fluvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, and ospemifene.
  • the term“endocrine therapeutic” refers to a compound that is effective for modulating hormone activityin a subject.Use ofan endocrine therapeutic in treatment ofa subject is “endocrine therapy”.Modulation ofhormone activitybyan endocrine therapeutic mayinclude increasing, decreasing, blocking, removing, or otherwise changing the level ofa hormone or the level ofactivityofa hormone.
  • Endocrine therapeutics include antiestrogens, aromatase inhibitors, SERMs, fluvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, and testolactone.
  • estrogen receptor or“ER” refers to an established member ofthe nuclear receptor familyofreceptors whichis a transcription factor activated bybinding ligands suchas the hormones 17 ⁇ -estradiol, estriol, estrone, etc.
  • “estrogen receptor” or“ER” refers to a nuclear receptor whichis a transcription factor activated bybinding ligands suchas the hormones 17 ⁇ -estradiol, estriol, and/or estrone.
  • “estrogen receptor” or“ER” refers to a nuclear receptor which is a transcription factor activated by binding the hormone 17 ⁇ - estradiol.
  • the term“estrogen receptor” mayrefer to the nucleotide sequence or protein sequence ofhuman estrogen receptor.
  • the term“estrogen receptor” mayrefer to the nucleotide sequence or protein sequence of human estrogen receptor 1 (a.k.a.
  • ER-alpha, ERalpha, or ER ⁇ e.g., Entrez2099, Uniprot P03372, RefSeqNM_000125, OMIM 133430, NP_000116, NP_000116.2, NM_000125.3, GI:62821794, and/or GI: 170295798).
  • the term“estrogen receptor” mayrefer to the nucleotide sequence or protein sequence ofhuman estrogen receptor 2 (a.k.a.ER-beta, ERbeta, or ER ⁇ ) (e.g., Entrez 2100, Uniprot Q92731, RefSeq NM_001040275, OMIM 601663, and/or GI: 94538324).
  • “estrogen receptor” is wild-type estrogen receptor.
  • “estrogen receptor” is wild-
  • an estrogen receptor is the wildtype human ER ⁇ . In embodiments, an estrogen receptor is the wildtype human ER ⁇ or ER ⁇ . In embodiments, an estrogen receptor is the wildtype human ER ⁇ and ER ⁇ . In embodiments, the estrogen receptor is a mutant estrogen receptor.In embodiments, the mutant estrogen receptor is associated witha disease that is not associated withwildtype estrogen receptor (e.g., drug resistant cancer). In embodiments, the estrogen receptor includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations)compared to the sequence above.
  • the estrogen receptor includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations)compared to the sequence above.
  • dose refers, in the usual and customarysense, to the amount ofactive ingredient given to an individual at eachadministration.
  • the dose maygenerallyrefer to the amount ofdisease treatment.
  • a dosage form refers to the particular format ofthe composition, active compound, pharmaceutical or pharmaceutical composition, and depends on the route ofadministration.
  • a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.
  • a composition can contain a pluralityofactive ingredients (e.g., two active ingredients)in a pluralityofseparate dosage forms (e.g., a separate dosage form for eachoftwo active ingredients).
  • a composition can contain a single dosage form (e.g., a single pill, tablet injection
  • CDK4 inhibitor and the like refer, in the usual and customarysense, to a compound whichinhibits the function ofCDK4.
  • the term“CDK4” refer, in the usual and customarysense, to cyclin-dependent kinase 4, as well known in the art.
  • the term“CDK6 inhibitor”and the like refer, in the usual and customarysense, to a compound whichinhibits the function ofCDK6.
  • CDK6 refer, in the usual and customarysense, to cyclin- dependent kinase 6, as well known in the art.
  • the terms“CDK 4/6 inhibitor”and the like refer, in the usual and customarysense, to a compound whichinhibits the function ofeither CDK4 or CDK6, or bothCDK4 and CDK6.
  • ExemplaryCDK 4/6 inhibitors include palbociclib (PD- 0332991), ribociclib (LEE011)and abemaciclib (LY2835219), se
  • synergy refers to a measured effect ofcompounds administered in combination where the measured effect is greater than the sum ofthe individual effects ofeachofthe compounds administered alone as a single agent.
  • a “combined synergistic amount” as used herein refers to the sum of a first amount (e.g., an amount ofa compound described herein)and a second amount (e.g., an amount ofa CDK4 inhibitor or a CDK6 inhibitor)that results in a synergistic effect (i.e.an effect greater than an additive effect).
  • compositions whichincludes a further agent or additional agent as defined herein, suchas a CDK4 inhibitor or a CDK6 inhibitor, and a compound, or a pharmaceuticall acceptable salt thereof, havin the formula
  • R 1 is independentlya hydrogen, halogen, -NR 2 R 3 , -CX a
  • R 2 is independentlya hydrogen, halogen, -CX b
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independentlyhydrogen,
  • the composition is provided as a single dosage form including both a CDK 4 inhibitor or a CDK 6 inhibitor in combination with a compound ofFormula (I).
  • the composition is provided as a pluralityofdosage forms, eachdosage form including a CDK 4 inhibitor or a CDK 6 inhibitor, and a compound ofFormula (I).
  • the compound has the structure offormula (I):
  • R 1 is independentlya hydrogen
  • R 2 is independentlya hydrogen, halogen,
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • L is independentlya bond, -NR 4 -, -NR 4 C(O)-, -C(O)NR 4 -, -O-, -S-,– C(O)-, -S(O)-,
  • R 4 is independentlya hydrogen, halogen, -CX d
  • n1, n2, n3, and n4 are independentlyan integer from 0 to 4.
  • the symbols X, X a , X b , X c and X d are independently–Cl, -Br, -I, or -F.
  • the compound has the formula (I):
  • R 1 is independentlya hydrogen
  • R 2 is independentlya hydrogen
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • L is independentlya bond, -NR 4 -, -NR 4 C(O)-, -C(O)NR 4 -, -O-, -S-,–C(O)-, -S(O)-, -S(O) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted substituted or unsubstituted
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independentlyhydrogen,
  • n1, n2, n3, and n4 are independentlyan integer from 0 to 4.
  • the symbols X, X a , X b , X c and X d are independently–Cl, -Br, -I, or -F. [0140]
  • the compound has the formula (1a):
  • the compound has the formula (II):
  • the compound has the formula(IIa):
  • the compound has the formula (IIb):
  • R 1 is independentlyhalogen, -NR 2 R 3 , -CX a
  • R 1 is independentlyhydrogen.In embodiments, R 1 is independently-NR 2 R 3 .In embodiments, R 1 is independently–NH 2 .In embodiments, R 1 is independently-CF 3 .In embodiments, R 1 is independently-CCl 3 .In embodiments, R 1 is independently-N(O) 2 .In embodiments, R 1 is independentlyhalogen.In embodiments, R 1 is independently-F.In embodiments, R 1 is independently-Cl.In embodiments, R 1 is independently-Br.In embodiments, R 1 is independently-I.In embodiments, R 1 is independentlysubstituted or unsubstituted cycloalkyl, substituted
  • R 1 is independentlysubstituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 1 is independentlyunsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 1 is independentlysubstituted or unsubstituted C 3 -C 7 cycloalkyl. In embodiments, R 1 is
  • R 1 is independentlyunsubstituted C 3 -C 7 cycloalkyl.
  • R 1 is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 1 is independently unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 1 is independently substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 1 is independentlyunsubstituted 3 to 7 membered heterocycloalkyl.
  • R 1 is independentlysubstituted or unsubstituted C 6 -C 12 aryl.
  • R 1 is independently unsubstituted C 6 -C 12 aryl.
  • R 1 is independentlysubstituted or unsubstituted C 6 - C 10 aryl.
  • R 1 is independentlyunsubstituted C 6 -C 10 aryl.
  • R 1 is independentlysubstituted C 6 -C 10 aryl.
  • R 1 is independentlydimethylaminoethyl. In embodiments, R 1 is independentlydimethylaminopropyl. In embodiments, R 1 is independentlyethylmorpholinyl. In embodiments, R 1 is independentlymorpholinyl. [0148] In embodiments, R 2 is independentlyhalogen, -CX b
  • R 2 is independentlyhydrogen. In embodiments, R 2 is independentlyhalogen. In embodiments, R 2 is independentlysubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 2 is independentlysubstituted or unsubstituted C 1 -C 12 alkyl. In embodiments, R 2 is independentlyunsubstituted C 1 -C 12 alkyl. In embodiments, R 2 is
  • R 2 independentlysubstituted or unsubstituted C 1 -C 8 alkyl.
  • R 2 is independently unsubstituted C 1 -C 8 alkyl.
  • R 2 is independentlysubstituted or unsubstituted C 1 - C 4 alkyl.
  • R 2 is independentlyunsubstituted C 1 -C 4 alkyl.
  • R 2 is independentlyunsubstituted methyl.
  • R 2 is independentlyunsubstituted ethyl.
  • R 2 is independentlyunsubstituted propyl. In embodiments, R 2 is independently substituted or unsubstituted 2 to 12 membered heteroalkyl. In embodiments, R 2 is independently unsubstituted 2 to 12 membered heteroalkyl.In embodiments, R 2 is independentlysubstituted or unsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 2 is independentlyunsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 2 is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 2 is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 2 is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.In embodiments, R 2 is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substitute
  • R 3 is independentlyhydrogen. In embodiments, R 3 is independentlyhalogen. In embodiments, R 3 is independentlysubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is independentlysubstituted or unsubstituted C 1 -C 12 alkyl. In embodiments, R 3 is independentlyunsubstituted C 1 -C 12 alkyl. In embodiments, R 3 is
  • R 3 independentlysubstituted or unsubstituted C 1 -C 8 alkyl.
  • R 3 is independently unsubstituted C 1 -C 8 alkyl.
  • R 3 is independentlysubstituted or unsubstituted C 1 - C 4 alkyl.
  • R 3 is independentlyunsubstituted C 1 -C 4 alkyl.
  • R 3 is independentlyunsubstituted methyl.
  • R 3 is independentlyunsubstituted ethyl.
  • R 3 is independentlyunsubstituted propyl. In embodiments, R 3 is independently substituted or unsubstituted 2 to 12 membered heteroalkyl. In embodiments, R 3 is independently unsubstituted 2 to 12 membered heteroalkyl.In embodiments, R 3 is independentlysubstituted or unsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 3 is independentlyunsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 3 is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 3 is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.In embodiments, R 3 is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substitute
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 2 and R 3 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.
  • R 2 and R 3 substituents are joined to form an unsubstituted heterocycloalkyl.
  • R 2 and R 3 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 2 and R 3 substituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 2 and R 3 substituents are joined to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 2 and R 3 substituents are joined to form an unsubsti
  • R 2 and R 3 substituents are joined to form a substituted or unsubstituted heteroaryl. In embodiments, R 2 and R 3 substituents are joined to form an unsubstituted heteroaryl. In embodiments, R 2 and R 3 substituents are joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl.In embodiments, R 2 and R 3 substituents are joined to form an unsubstituted 5 to 10 membered heteroaryl.In embodiments, R 2 and R 3 substituents are joined to form a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 2 and R 3 substituents are joined to form an unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 2 and R 3 substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R 2 and R 3 substituents are joined to form
  • Lis independentlya bond, -NR 4 -, -NR 4 C(O)-, -C(O)NR 4 -, -O-, -S-, –C(O)-, -S(O)-, -S(O) 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • Lis independentlya bond.
  • Lis Lis
  • Lis independentlysubstituted or unsubstituted C 1 -C 12 alkylene In embodiments, Lis independentlyunsubstituted C 1 -C 12 alkylene.In embodiments, Lis independentlysubstituted or unsubstituted C 1 -C 8 alkylene.In embodiments, Lis independently unsubstituted C 1 -C 8 alkylene.In embodiments, Lis independentlysubstituted or unsubstituted C 1 -C 6 alkylene.In embodiments, Lis independentlyunsubstituted C 1 -C 6 alkylene.In embodiments, Lis independentlysubstituted or unsubstituted C 1 -C 4 alkylene.In embodiments, L is independentlyunsubstituted C 1 -C 4 alkylene.In embodiments, Lis independentlyunsubstituted methylene.In embodiments, Lis independentlyunsubstituted ethylene.In embodiments, Lis independentlyunsubstituted ethylene.In embodiment
  • L is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkylene.
  • L is independentlyunsubstituted 2 to 12 membered heteroalkylene.
  • L is independentlyunsubstituted 2 to 8 membered heteroalkylene.
  • L is independentlyunsubstituted 2 to 6 membered heteroalkylene.
  • L is independentlyunsubstituted 2 to 4 membered heteroalkylene.
  • R 4 is independentlyhydrogen.
  • R 4 is independentlysubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 4 is independentlysubstituted or unsubstituted C 1 -C 12 alkyl. In embodiments, R 4 is independentlyunsubstituted C 1 -C 12 alkyl. In embodiments, R 4 is
  • R 4 independentlysubstituted or unsubstituted C 1 -C 8 alkyl.
  • R 4 is independently unsubstituted C 1 -C 8 alkyl.
  • R 4 is independentlysubstituted or unsubstituted C 1 - C 4 alkyl.
  • R 4 is independentlyunsubstituted C 1 -C 4 alkyl.
  • R 4 is independentlyunsubstituted methyl.
  • R 4 is independentlyunsubstituted ethyl.
  • R 4 is independentlyunsubstituted propyl. In embodiments, R 4 is independently substituted or unsubstituted 2 to 12 membered heteroalkyl.In embodiments, R 4 is independently unsubstituted 2 to 12 membered heteroalkyl.In embodiments, R 4 is independentlysubstituted or unsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 4 is independentlyunsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 4 is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 4 is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.In embodiments, R 4 is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substitute
  • R 4 is independentlyunsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 4 is independentlysubstituted or unsubstituted C 3 -C 7 cycloalkyl. In embodiments, R 4 is
  • R 4 is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 4 is independentlyunsubstituted 3 to 8 membered heterocycloalkyl.In embodiments, R 4 is independentlysubstituted or unsubstituted 3 to 7 membered heterocycloalkyl.In embodiments, R 4 is independentlyunsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R 4 is independentlysubstituted or 3 to 7 membered heterocycloalkyl. In embodiments, R 4 is independentlysubstituted or unsubstituted C 6 -C 12 aryl. In embodiments, R 4 is independentlyunsubstituted C 6 -C 12 aryl. In embodiments, R4 is independentlysubstituted or unsubstituted C 6 -C 10 aryl.In embodiments, R 4 is independently unsubstituted C 6 -C 10 aryl.In embodiments
  • R 5 is independentlyhydrogen.
  • R 5 is independentlysubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is independently–NH 2 .
  • R 5 is independently-CF 3 .
  • R 5 is independently-CCl 3 .
  • R 5 is independently-N(O) 2 .
  • R 5 is independently-Br.In embodiments, R 5 is independently-I.In
  • R 5 is independentlysubstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0161] In embodiments, R 5 is independentlysubstituted or unsubstituted C 1 -C 12 alkyl. In embodiments, R 5 is independentlyunsubstituted C 1 -C 12 alkyl.In embodiments, R 5 is
  • R 5 independentlysubstituted or unsubstituted C 1 -C 8 alkyl.
  • R 5 is independently unsubstituted C 1 -C 8 alkyl.
  • R 5 is independentlysubstituted or unsubstituted C 1 - C 4 alkyl.
  • R 5 is independentlyunsubstituted C 1 -C 4 alkyl.
  • R 5 is independentlyunsubstituted methyl.
  • R 5 is independentlyunsubstituted ethyl.
  • R 5 is independentlyunsubstituted propyl. In embodiments, R 5 is independently substituted or unsubstituted 2 to 12 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted 2 to 12 membered heteroalkyl.In embodiments, R 5 is independentlysubstituted or unsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 5 is independentlyunsubstituted 2 to 8 membered heteroalkyl.In embodiments, R 5 is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 5 is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.In embodiments, R 5 is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substitute
  • R 5 is independentlyunsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R 5 is independentlysubstituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 5 is
  • R 5 is independentlyunsubstituted C 3 -C 8 cycloalkyl.
  • R 5 is independentlysubstituted or unsubstituted C 3 -C 7 cycloalkyl.
  • R 5 is independentlyunsubstituted C 3 -C 7 cycloalkyl.
  • R 5 is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 5 is independentlyunsubstituted 3 to 8 membered heterocycloalkyl.
  • R 5 is independentlysubstituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 5 is independentlyunsubstituted 3 to 7 membered heterocycloalkyl.
  • R 5 is independentlysubstituted or unsubstituted C 6 -C 12 aryl. In embodiments, R 5 is independentlyunsubstituted C 6 -C 12 aryl. In embodiments, R 5 is
  • R 5 is independentlysubstituted or unsubstituted C 6 -C 10 aryl.
  • R 5 is independently unsubstituted C 6 -C 10 aryl.
  • R 5 is independentlysubstituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 5 is independentlyunsubstituted 5 to 10 membered heteroaryl.
  • R 5 is independentlysubstituted or unsubstituted 5 to 9 membered heteroaryl.
  • R 5 is independentlyunsubstituted 5 to 9 membered heteroaryl.
  • R 5 is independently-CX e
  • R 5 is
  • R 5 is independently -CN.
  • R 5 is independently-SO 2 Cl.
  • R 5 is independently-SO n5 R 26 .
  • R 5 is independently-SO v5 NR 23 R 24 .
  • R 5 is independently -NHNH 2 .
  • R 5 is independently -ONR 23 R 24 .
  • R 5 is independently-OR 26 .
  • R 5 is independently-NR 23 SO 2 R 26 .
  • R 5 is independently- NR 23 C(O)-OR 25 .
  • R 5 is independently-NR 23 OR 25 .
  • R 5 is independently-OCX e
  • R 5 is independentlya hydrogen, halogen, -CX e
  • R 5 is independentlya hydrogen, -F, -CF 3 , or unsubstituted methyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted C 1 - C 4 alkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted C 1 -C 4 alkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted 2 to 12 membered heteroalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted methyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted C 3 -C 8 cycloalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted 3 to 8 membered heterocycloalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independently substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted C 6 -C 12 aryl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independently unsubstituted C 6 -C 12 aryl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlysubstituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , or R 26 is independentlyunsubstituted 5 to 10 membered heteroaryl.
  • R 11 and R 12 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.
  • R 11 and R 12 substituents are joined to form an unsubstituted heterocycloalkyl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 11 and R 12 substituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 11 and R 12 substituents are joined to form an unsubsti
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 11 and R 12 substituents are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. [0172] In embodiments, R 11 and R 12 substituents are joined to form a substituted or
  • R 11 and R 12 substituents are joined to form an unsubstituted heteroaryl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 11 and R 12 substituents are joined to form an unsubstituted 5 to 10 membered heteroaryl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • R 11 and R 12 substituents are joined to form an unsubstituted 5 to 9 membered heteroaryl.
  • R 11 and R 12 substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 15 and R 16 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl. In embodiments, R 15 and R 16 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.In embodiments, R 15 and R 16 substituents are joined to form an unsubstituted heterocycloalkyl. In embodiments, R 15 and R 16 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 15 and R 16 substituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 15 and R 16 substituents are joined to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.In embodiments, R 15 and R 16 substituents are joined to form an unsubsti
  • R 15 and R 16 substituents are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 15 and R 16 substituents are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. [0174] In embodiments, R 15 and R 16 substituents are joined to form a substituted or
  • R 15 and R 16 substituents are joined to form an unsubstituted heteroaryl.
  • R 15 and R 16 substituents are joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 15 and R 16 substituents are joined to form an unsubstituted 5 to 10 membered heteroaryl.
  • R 15 and R 16 substituents are joined to form a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • R 15 and R 16 substituents are joined to form an unsubstituted 5 to 9 membered heteroaryl.
  • R 15 and R 16 substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 19 and R 20 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.
  • R 19 and R 20 substituents are joined to form an unsubstituted heterocycloalkyl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 19 and R 20 substituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 19 and R 20 substituents are joined to form an unsubsti
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 19 and R 20 substituents are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. [0176] In embodiments, R 19 and R 20 substituents are joined to form a substituted or
  • R 19 and R 20 substituents are joined to form an unsubstituted heteroaryl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 19 and R 20 substituents are joined to form an unsubstituted 5 to 10 membered heteroaryl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • R 19 and R 20 substituents are joined to form an unsubstituted 5 to 9 membered heteroaryl.
  • R 19 and R 20 substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 23 and R 24 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 23 and R 24 substituents are joined to form a substituted or unsubstituted heterocycloalkyl.
  • R 23 and R 24 substituents are joined to form an unsubstituted heterocycloalkyl.
  • R 23 and R 24 substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 23 and R 24 substituents are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 23 and R 24 substituents are joined to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • R 23 and R 24 substituents are joined to form an unsubsti
  • R 23 and R 24 substituents are joined to form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 23 and R 24 substituents are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl. [0178] In embodiments, R 23 and R 24 substituents are joined to form a substituted or
  • n is 0.In embodiments, n is 1.In embodiments, n is 2.In
  • n is 3.In embodiments, n is 4.In embodiments, n is 5.In embodiments, m1 is 1. In embodiments, m1 is 2.In embodiments, m2 is 1.In embodiments, m2 is 2.In embodiments, m3 is 1.In embodiments, m3 is 2.In embodiments, m4 is 1.In embodiments, m4 is 2.In embodiments, m5 is 1.In embodiments, m5 is 2.In embodiments, v1 is 1.In embodiments, v1 is 2.In embodiments, v2 is 1.In embodiments, v2 is 2.In embodiments, v3 is 1.In
  • v3 is 2.In embodiments, v4 is 1.In embodiments, v4 is 2.In embodiments, v5 is 1.In embodiments, v5 is 2.In embodiments, n1 is 0.In embodiments, n1 is 1.In embodiments, n1 is 1.In embodiments, v3 is 2.In embodiments, v4 is 1.In embodiments, v4 is 2.In embodiments, v5 is 1.In embodiments, v5 is 2.In embodiments, n1 is 0.In embodiments, n1 is 1.In
  • n1 is 2.In embodiments, n1 is 3.In embodiments, n1 is 4.In embodiments, n2 is 0.In embodiments, n2 is 1.In embodiments, n2 is 2.In embodiments, n2 is 3.In
  • n2 is 4.In embodiments, n3 is 0.In embodiments, n3 is 1.In embodiments, n3 is 2.In embodiments, n3 is 3.In embodiments, n3 is 4.In embodiments, n4 is 0.In
  • n4 is 1.In embodiments, n4 is 2.In embodiments, n4 is 3.In embodiments, n4 is 4.In embodiments, n5 is 0.In embodiments, n5 is 1.In embodiments, n5 is 2.In
  • n5 is 3.In embodiments, n5 is 4. [0180]
  • X is independently–Cl.In embodiments, X is independently-Br.In embodiments, X is independently-I.In embodiments, X is independently-F.In embodiments, X a is independently–Cl.In embodiments, X a is independently-Br.In embodiments, X a is independently-I.In embodiments, X a is independently-F.In embodiments, X b is independently –Cl.In embodiments, X b is independently-Br.In embodiments, X b is independently-I.In embodiments, X b is independently-F.In embodiments, X c is independently–Cl.In
  • X c is independently-Br.In embodiments, X c is independently-I.In
  • X c is independently-F.
  • X d is independently–Cl.In
  • X d is independently-Br.In embodiments, X d is independently-I.In
  • X d is independently-F.
  • X e is independently–Cl.In
  • X e is independently-Br.In embodiments, X e is independently-I.In
  • X e is independently-F.
  • R 1 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 27 -substituted or unsubstituted aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • R 27 -substituted or unsubstituted heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 27 is independentlyoxo
  • R 27 is piperidine. In embodiments, R 27 is piperazine.In embodiments, R 27 is pyridine.In embodiments, R 27 is pyrazine.In embodiments, R 27 is dimethylamino.In embodiments, R 27 is dimethylaminoethyl.In embodiments, R 27 is dimethylaminopropyl.In embodiments, R 27 is ethylmorpholinyl.In embodiments, R 27 is morpholinyl. [0183] R 28 is independentlyoxo,
  • R 28 is piperidine. In embodiments, R 28 is piperazine.In embodiments, R 28 is pyridine.In embodiments, R 28 is pyrazine.In embodiments, R 28 is dimethylamino.In embodiments, R 28 is dimethylaminoethyl.In embodiments, R 28 is dimethylaminopropyl.In embodiments, R 28 is ethylmorpholinyl.In embodiments, R 28 is morpholinyl.
  • R 2 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 31 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 32 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 32 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 32 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 32 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 3 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 34 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 34 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 34 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 35 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 35 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 35 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 35 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 4 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 37 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 37 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 37 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 38 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 38 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 38 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 38 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 5 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 40 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 40 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 40 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 41 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 41 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 41 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 41 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 9 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 43 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 43 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 43 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 44 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 44 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 44 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 44 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 10 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 46 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 46 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 46 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 47 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 47 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 47 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 47 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 11 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 49 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 49 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 49 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 50 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 50 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 50 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 50 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 12 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 52 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 52 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 52 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 53 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 53 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 53 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 53 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 13 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 55 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 55 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 55 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 56 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 56 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 56 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 56 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 14 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 58 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 58 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 58 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 59 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 59 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 59 -substituted or unsubstituted aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • R 59 - substituted or unsubstituted heteroaryl e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 15 is independentlyhydrogen, oxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 61 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 61 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 61 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 62 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 62 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 62 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 62 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 16 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 64 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 64 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 64 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 65 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 65 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 65 -substituted or unsubstituted aryl (e.g.C 6 -C 10 aryl or C 6 aryl), or R 65 - substituted or unsubstituted heteroaryl (e.g.5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 17 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 67 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 67 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 67 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 68 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 68 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 68 -substituted or unsubstituted aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • R 68 - substituted or unsubstituted heteroaryl e.g.5 to
  • R 18 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 70 -substituted or unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 70 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 70 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 70 is independentlyoxo,
  • unsubstituted heteroalkyl e.g.2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 71 -substituted or unsubstituted cycloalkyl e.g.C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 71 -substituted or unsubstituted heterocycloalkyl e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 71 -substituted or unsubstituted aryl e.g.C 6 -C 10 aryl or C 6 aryl
  • R 71 - substituted or unsubstituted heteroaryl e.g.5 to
  • R 19 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 20 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 21 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 22 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 23 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 24 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 25 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • R 26 is independentlyhydrogen, oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 ,
  • Lis independentlya bond, R 80 -substituted or unsubstituted alkylene, R 80 -substituted or unsubstituted heteroalkylene, R 80 -substituted or unsubstituted cycloalkylene, R 80 -substituted or unsubstituted heterocycloalkylene, R 80 -substituted or unsubstituted arylene, or R 80 -substituted or unsubstituted heteroarylene.
  • R 29 , R 32 , R 35 , R 38 , R 41 , R 44 , R 47 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , and R 80 are independentlyoxo,
  • the compound is a compound described herein.In some embodiments, the compound is a compound described herein.In some embodiments, the compound is a compound described herein.In some
  • the compound is not a compound selected from JD101 to JD160 (e.g., JD101, JD102, JD103, JD104, JD105, JD106, JD107, JD108, JD109, JD110, JD111, JD112, JD113, JD114, JD115, JD116, JD117, JD118, JD119, JD120, JD121, JD122, JD123, JD124, JD125, JD126, JD127, JD128, JD129, JD130, JD131, JD132, JD133, JD134, JD135, JD136, JD137, JD138, JD139, JD140, JD141, JD142, JD143, JD144, JD145, JD146, JD147, JD148, JD149, JD150, JD151, JD152, JD153, JD154, JD155, JD156, JD157, JD
  • a compound as described herein mayinclude multiple instances ofR 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , m1, m2, m3, m4, m5, v1, v2, v3, v4, v5, n1, n2, n3, n4, n5, X, X a , X b , X c , X d and X e , and/or other variables.
  • eachvariable mayoptional be different and be appropriately labeled to distinguisheachgroup for greater clarity.For example, where eachR 1 , R 2 , R 3 , R 4 , R 5 , R 9
  • the compound competes withestrogen for binding to estrogen receptor (ER).
  • the compound competes with4-hydroxytamoxifen for binding to ER.
  • the compound binds the ligand binding domain ofER.
  • the compound modulates the conformation ofhelix12 ofER relative to the conformation ofhelix12 when estrogen is bound to ER.
  • the compound modulates (e.g., reduces relative to estrogen bound ER)the binding ofER to estrogen response elements.
  • the compound modulates (e.g., reduces relative to estrogen bound ER)the phosphorylation ofER.
  • the compound modulates (e.g., reduces relative to estrogen bound ER)the activity ofa cellular pathway(e.g., ras-MAPK containing pathway, PI3K/AKTcontaining pathway, Shc containing pathway, Src kinase containing pathway, JAK/STATcontaining pathway, nitric oxide synthase pathway
  • the composition includes a CDK4 inhibitor.In embodiments, the composition does not include a CDK6 inhibitor.In embodiments, the composition includes a CDK6 inhibitor.In embodiments, the composition does not include a CDK4 inhibitor. [0241] In accordance withthe aspects ofthe present disclosure, it was unexpectedlyand surprisinglyfound that the compounds described herein synergizes withan amount ofa CDK4 inhibitor or a CDK6 inhibitor to elicit enhanced inhibition ofcell proliferation ofcancer cells, suchas NSCLC cells, as compared to when used individuallyand separately(i.e., monotherapy treatment). [0242] In embodiments, the compound and the CDK4 inhibitor are present in the composition in a synergistic amount.
  • the compound and the CDK6 inhibibor are present in the composition in a synergistic amount.
  • a synergistic amount maybe about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,
  • a synergistic amount maybe about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.
  • the synergistic effect maybe a compound activitydecreasing effect and/or a CDK4 inhibitor or CDK6 inhibitor decreasing effect.
  • synergybetween the compound and the CDK4 inhibitor or the CDK6 inhibitor mayresult in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4
  • compositions including a pharmaceuticallyacceptable excipient, a further agent or additional agent as defined herein, such as a CDK4 inhibitor or a CDK6 inhibitor, and a compound, or pharmaceuticallyacceptable salt thereof, as described herein, including embodiments (e.g.compound offormula I, Ia, Ib, II, IIa, IIb, or anyembodiment thereof, or in an example, table, figure, or claim).
  • the compound is a compound selected from JD101 to JD160, as disclosed herein.
  • the CDK4 inhibitor or CDK6 inhibitor, and the compound, or pharmaceuticallyacceptable salt thereof, as described herein are eachincluded in a
  • the pharmaceutical composition includes an additional agent or further agent (e.g.therapeutic agent).
  • the pharmaceutical composition includes a further agent (e.g. therapeutic agent)in a therapeuticallyeffective amount.
  • the further agent is an agent for treating cancer (an anti-cancer agent).
  • the further agent is an agent for treating a hyperproliferative disorder.
  • the further agent is an anti-cancer agent.
  • the further agent is a chemotherapeutic.
  • the further agent is an agent for treating breast cancer.
  • the further agent is an agent for treating lung cancer.
  • the further agent is an agent for treating a gynecological cancer.
  • the further agent is an agent for treating ovarian cancer.
  • the further agent is an agent for treating endometrial cancer.
  • the further agent is an agent for treating prostate cancer
  • the further agent is an aromatase inhibitor.
  • the further agent is a HER-2 inhibitor.
  • the further agent is Herceptin.
  • the further agent is fulvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, or testolactone.
  • the further agent is tamoxifen.
  • the further agent is an EGFR inhibitor (e.g.gefitinib (IressaTM), erlotinib (Tarceva TM), cetuximab (ErbituxTM), lapatinib (TYKERBTM), panitumumab (VECTIBIXTM), vandet
  • EGFR inhibitor e.g.gefit
  • the further agent is a mammalian target ofrapamycin (mTOR) inhibitor (suchas everolimus)for use in treating cancer (e.g.in breast and NSCLC tumors); HER2-targeted therapeutics (suchas trastuzumab, lapatinib, trastuzumab- emtansine)for use in treating cancer (e.g.ER-positive breast cancers withoverexpression ofHER-2 receptors);HER3- targeted agents (e.g.pertuzumab);EGFR-targeted therapeutics (suchas erlotinib, gefitinib, afitinib)for treating cancer (e.g.NSCLC expressing mutant EGFR or having EGFR-positivity); tamoxifen or aromatase inhibitors
  • mTOR mammalian target ofrapamycin
  • HER2-targeted therapeutics suchas trastuzumab, lapatinib, trastuzumab- emtansine
  • kits including a further agent or additional agent as defined herein, suchas a CDK4 inhibitor or a CDK6 inhibitor, and a compound as disclosed herein (e.g., a compound having the structure ofFormula I’, I, Ia, Ib, II, IIa, IIb), or
  • kits including a CDK4 inhibitor or a CDK6 inhibitor;and a
  • R 1 is independentlya hydrogen, halogen, -NR 2 R 3 , -CX a
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  • R 4 is independentlya hydrogen, halogen, -CX d
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independentlyhydrogen,
  • the kit further includes instructions for pharmaceutical use.
  • the compound and the CDK4 inhibitor are present in the kit in a synergistic amount.
  • the compound and the CDK6 inhibibor are present in the kit in a synergistic amount.
  • a method for treating a hyperproliferative disorder in a subject in need thereof including administering to the subject an effective amount ofa composition disclosed herein;or the compound and the further agent (e.g.the CDK4 inhibitor or CDK6 inhibitor)ofthe kit as disclosed herein.
  • the method includes administering a compound provided herein suchas a comfpounfofFormula Iand embodiments thereof, and an additional agent or further agent, suchas a CDK4 inhibitor or CDK6 inhibitor.
  • the hyperproliferative disorder is associated withestrogen receptor activity.
  • the hyperproliferative disorder is lymphangioleiomyomatosis.
  • the hyperproliferative disorder is a cancer.
  • the hyperproliferative disorder is a cancer resistant to an anti-cancer agent (e.g., tamoxifen, an antiestrogen, an aromatase inhibitor).
  • the cancer is breast cancer.
  • the cancer is breast cancer, lung cancer, a gynecological cancer, ovarian cancer, endometrial cancer, or prostate cancer.
  • the cancer is ER positive breast cancer.
  • the cancer is ER negative breast cancer.
  • the cancer is hormone sensitive breast cancer.
  • the cancer is hormone insensitive breast cancer.
  • the cancer is triple negative breast cancer.
  • the cancer is HER-2 positive breast cancer.
  • the cancer is metastatic breast cancer.In embodiments, the
  • the hyperproliferative disorder is a cancer ofan estrogen target organ or tissue.
  • the cancer is non-small cell lung cancer.
  • the cancer is small cell lung cancer.
  • the lung cancer is adenocarcinoma.
  • the lung cancer is squamous-cell carcinoma.
  • the lung cancer is large-cell carcinoma.
  • the lung cancer is bronchioloalveolar carcinoma.
  • the lung cancer is stage I.In embodiments, the lung cancer is stage II.In embodiments, the lung cancer is stage III.In embodiments, the lung cancer is stage IV.
  • the method or use includes administering a further agent (e.g.therapeutic agent).
  • a further agent e.g.therapeutic agent
  • the method or use includes administering a further agent (e.g.therapeutic agent)in a therapeuticallyeffective amount.
  • the further agent is an agent for treating cancer.
  • the further agent is an agent for treating a therapeuticallyeffective amount.
  • the further agent is an anti-cancer agent. In embodiments, the further agent is a chemotherapeutic.In embodiments, the further agent is an agent for treating breast cancer.In embodiments, the further agent is an agent for treating lung cancer.In embodiments, the further agent is an agent for treating a gynecological cancer.In embodiments, the further agent is an agent for treating ovarian cancer.In embodiments, the further agent is an agent for treating endometrial cancer.In embodiments, the further agent is an agent for treating prostate cancer. In embodiments, the further agent is an agent for treating lymphangioleiomyomatosis (LAM).In embodiments, the further agent is an agent for inhibiting estrogen receptor activity.In embodiments, the further agent is an agent for treating a disease associated withestrogen receptor activity.In embodiments, the further agent is an antiestrogen.
  • the further agent is a chemotherapeutic.In embodiments, the further agent is an agent for treating breast cancer.In embodiments, the further agent is an agent for treating lung cancer.In
  • the further agent is an aromatase inhibitor.
  • the further agent is an endocrine therapeutic.
  • the further agent is an anti-cancer agent.
  • the further agent is a chemotherapeutic.
  • the further agent is a HER-2 inhibitor.
  • the further agent is fulvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, aminoglutethimide, or testolactone.
  • the further agent is tamoxifen.
  • the method or use does not include an increased riskofendometrial cancer.
  • the method or use does not include an increased riskofa gynecological cancer.
  • the method includes administration of a further agent in combination withthe compounds provided herein suchas the compound ofFormula I(or pharmaceutically acceptable salt thereof).
  • the further agent is an anti-cancer compound as disclosed herein.
  • the further agent is Buparlisib (BKM120), Pietilisib
  • the further agent is Buparlisib (BKM120), BAY80-6946, Taselisib (GDC0032), Alpelisib (BYL719), Idelalisib (CAL-101), or Duvelisib (IPI-145).
  • the further agent is an inhibitor ofPI3K,
  • the further agent is administered contemporaneouslywiththe composition or compound disclosed herein, or pharmaceuticallyacceptable salt thereof.
  • the further agent is administered sequentially.
  • the further agent e.g., tamoxifen, exemestane, letrozole, anastrazole or enzalutamide
  • the further agent is adriamycin, a taxane, cyclophosphamide, fluorouracil, methotrexate, cisplatin, or carboplatin.
  • the further agent is metformin or analog thereof, as known in the art.
  • the further agent is an NF -B inhibitor (e.g., parthenolides or parthenolide derivatives).
  • the further agent is an estrogen receptor-beta targeted agent.In embodiments, the further agent inhibits EGFR, HER2 and/or HER3.
  • compositions as described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination with a further agent for use in the treatment ofgynecomastia in a subject in need of suchtreatment.
  • the use includes administering to the subject a therapeuticallyeffective amount ofa composition described herein, or a compound as described herein or pharmaceutically acceptable salt thereofin combination with a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor).
  • the use mayinclude administering to the subject a therapeuticallyeffective amount ofa compound described herein in combination witha therapeuticallyeffective amount ofa further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor).
  • gynecomastia is associated withestrogen receptor activity.
  • gynecomastia is non-physiologic gynecomastia.
  • gynecomastia is physiologic gynecomastia.
  • the method or use improves (e.g.increases)bone densityrelative to the absence ofthe compound.
  • the method or use improves (e.g.increases)bone mass relative to the absence ofthe compound.
  • the method or use improves (e.g.
  • the method or use is a treatment for osteoporosis, osteogenesis imperfecta, or osteopenia. In embodiments, the method or use is a treatment for osteogenesis imperfecta. [0275] In embodiments, the method or use is used to prevent bone deterioration, prevent bone degradation, prevent bone degeneration, prevent loss ofbone mass, prevent loss ofbone density, stabilize bone deterioration, stabilize bone degradation, stabilize bone degeneration, stabilize the loss ofbone mass, stabilize the loss ofbone density, decrease bone deterioration, decrease bone degradation, decrease bone degeneration, decrease loss ofbone mass, decrease loss ofbone density, increase bone mass, increase bone density, or combinations thereof.
  • a method oftreating a bone disorder in a subject in need thereof including administering to the subject an effective amount ofa composition described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination with a further agent (e.g.a CDK 4 inhibitor or CDK 6 inhibitor).
  • a further agent e.g. a CDK 4 inhibitor or CDK 6 inhibitor.
  • use of a composition as described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination witha CDK 4 inhibitor or CDK 6 inhibitor in the manufacture ofa medicament for the treatment ofa bone disorder in a subject in need ofsuchtreatment.
  • a composition as described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination with a further agent for use in the treatment ofa bone disorder in a subject in need of suchtreatment.
  • the use includes administering to the subject a composition described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination with a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor).
  • the use mayinclude administering to the subject a therapeuticallyeffective amount ofa composition described herein, or a compound as described herein or pharmaceuticallyacceptable salt thereofin combination witha further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor).
  • the bone disorder is osteoporosis, osteogenesis imperfecta, or osteopenia.
  • the bone disorder is osteogenesis imperfecta.
  • the bone disorder is bone deterioration, bone degradation, bone degeneration, loss ofbone mass, loss ofbone density, or combinations thereof.
  • the method or use is used to prevent bone deterioration, prevent bone degradation, prevent bone degeneration, prevent loss ofbone mass, prevent loss ofbone density, stabilize bone deterioration, stabilize bone degradation, stabilize bone degeneration, stabilize the loss ofbone mass, stabilize the loss ofbone density, decrease bone deterioration, decrease bone degradation, decrease bone degeneration, decrease loss ofbone mass, decrease loss ofbone density, increase bone mass, increase bone density, or combinations thereof.
  • the method or use includes administering a compound described herein in combination with a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)as disclosed herein.
  • a further agent e.g.CDK 4 inhibitor or CDK 6 inhibitor
  • use of a compound as described or pharmaceuticallyaccept salt thereofand a further agent e.g.CDK 4 inhibitor or CDK 6 inhibitor)as disclosed herein in the manufacture ofa medicament for the treatment ofa hyperproliferative disorder in a subject in need ofsuchtreatment.
  • a compound as disclosed herein, or pharmaceuticallyaccept salt thereof, and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)as disclosed herein for use in the treatment ofa hyperproliferative disorder in a subject in need ofsuchtreatment includes administering to the subject a compound disclosed herein, or pharmaceutically accept salt thereof, and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor).
  • the use may include administering to the subject a therapeuticallyeffective amount ofa composition described herein.
  • the method for treating a hyperproliferative disorder includes the adiminstration ofa composition where the compound and the CDK4 inhibitor are present in the composition in a synergistic amount.
  • the method for treating a hyperproliferative disorder includes the adiminstration of a composition where the compound and the CDK6 inhibitor are present in the composition in a synergistic amount.
  • Methods of Inhibiting Estrogen Receptor [0286] In an aspect is provided a method ofinhibiting estrogen receptor activityin a subject in need thereof. The method includes administering to the subject an effective amount ofa composition as disclosed herein, or a compound or pharmaceuticallyacceptable salt thereofa further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)ofthe kit disclosed herein.Thus, in embodiments, the method includes administering a compound provided herein suchas a comfpounfofFormula Iand embodiments thereof, and an additional agent or further agent, such as a CDK4 inhibitor or CDK6 inhibitor.
  • the method or use includes modulation (e.g., inhibition or reduction) ofthe activityofa cellular pathway(e.g., ras-MAPK containing pathway, PI3K/AKTcontaining pathway, Shc containing pathway, Src kinase containing pathway, JAK/STATcontaining pathway, nitric oxide synthase pathway, VEGFsecretion pathway).
  • the method or use includes modulation (e.g., inhibition or reduction)ofDNA synthesis.
  • the method or use includes modulation (e.g., inhibition or reduction)ofcell growth.
  • the method or use includes modulation (e.g., inhibition or reduction)ofcell proliferation. In embodiments, the method or use includes modulation (e.g., inhibition or reduction)ofepithelial cell proliferation. In embodiments, the method or use includes modulation (e.g., activation or increasing)ofthe degradation ofER. In embodiments, the method or use includes modulation (e.g., activation or increasing)ofthe ubiquitination ofER. In embodiments, the method or use includes modulation (e.g., activation or increasing)ofthe degradation ofER bythe proteasome. In embodiments, the method or use includes modulation (e.g., inhibition or reduction) of ER interaction with AP-1, NF- ⁇ B, MAPK, PI3K, or AKT kinase.
  • the method or use includes modulation (e.g., inhibition or reduction)ofER phosphorylation.
  • the method or use includes modulation (e.g., activation or increasing)oftumor cell apoptosis.
  • the method or use includes modulation (e.g., activation or increasing)ofcancer cell apoptosis.
  • the method or use includes modulation (e.g., activation or increasing)ofER expressing cell apoptosis.
  • the method or use includes modulation (e.g., inhibition or reduction)ofER translocation to the nucleus.
  • the method or use includes modulation (e.g., inhibition or reduction)ofER translocation to the cytosol.
  • the method or use includes administering a composition described herein, or a compound or pharmaceuticallyacceptable salt thereof disclosed herein and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)disclosed herein.
  • a further agent e.g.CDK 4 inhibitor or CDK 6 inhibitor
  • use of a composition as described herein, or a compound or pharmaceuticallyacceptable salt thereofdisclosed herein and a further agent e.g.CDK 4 inhibitor or CDK 6 inhibitor
  • a composition as described herein, or a compound or pharmaceuticallyacceptable salt thereofdisclosed herein and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)disclosed herein, for use in inhibiting estrogen receptor activityin a subject in need ofsuchtreatment includes administering to the subject a composition, or a compound or pharmaceuticallyacceptable salt thereofdisclosed herein and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)disclosed herein described herein.
  • the use may include administering to the subject a therapeuticallyeffective amount ofa composition described herein, or a compound or pharmaceuticallyacceptable salt thereofdisclosed herein and a further agent (e.g.CDK 4 inhibitor or CDK 6 inhibitor)disclosed herein described herein.
  • the method ofinhibiting estrogen receptor activityin a subject includes the adiminstration of a composition where the compound and the CDK4 inhibitor are present in the composition in a synergistic amount.
  • the method ofinhibiting estrogen receptor activityin a subject includes the adiminstration of a composition where the compound and the CDK6 inhibitor are present in the composition in a synergistic amount.
  • Embodiment 1 A composition comprising: a CDK4 inhibitor or a CDK6 inhibitor;and
  • R 1 is independentlya hydrogen, halogen, -NR 2 R 3 , -CX a
  • heteroalkylene substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted
  • heteroarylene or a substituted or unsubstituted spirocyclic linker
  • R 2 is independentlya hydrogen, halogen, -CX b
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl;
  • R 4 is independentlya hydrogen, halogen, -CX d
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independently hydrogen, halogen, -CX 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, - SO 4 H,
  • n is an integer from 0 to 5;
  • n 1 or 2;
  • n1, n2, n3, and n4 are independentlyan integer from 0 to 4;
  • X, X a , X b , X c and X d are independently–Cl, -Br, -I, or -F.
  • Embodiment 2 The composition ofembodiment 1, the compound having the formula:
  • R 5 is independentlya hydrogen, halogen, -CX e
  • R 23 , R 24 , R 25 , and R 26 are independentlyhydrogen
  • n5 is independentlyan integer from 0 to 4.
  • Embodiment 3 The composition ofembodiment 2, wherein R 5 ofthe compound is independentlya hydrogen, halogen, -CX e
  • Embodiment 4 The composition ofembodiment 2, wherein R 5 ofthe compound is independentlya hydrogen, -F, -CF 3 , or unsubstituted methyl.
  • Embodiment 5 The composition ofembodiment 1, the compound having the formula:
  • Embodiment 6 The composition ofembodiment 1, the compound having the formula:
  • Embodiment 7 The composition ofembodiment 1, the compound having the formula:
  • R 5 is independentlya hydrogen, halogen, -CX e
  • R 23 , R 24 , R 25 , and R 26 are independentlyhydrogen
  • n5 is independentlyan integer from 0 to 4.
  • Embodiment 8 The composition ofembodiment 7, wherein R 5 ofthe compound is independentlya hydrogen, halogen, -CX e
  • Embodiment 9 The composition ofembodiment 7, wherein R 5 ofthe compound is independentlya hydrogen, -F, -CF 3 , or unsubstituted methyl.
  • Embodiment 10 The composition ofembodiment 1, the compound having the formula: IIb).
  • Embodiment 11 The composition ofembodiment 1, wherein Lofthe compound is a bond.
  • Embodiment 12 The composition ofembodiment 1, wherein Lofthe compound is a heteroalkylene.
  • Embodiment 13 The composition ofembodiment 1, wherein Lofthe compound is independentlya 2 to 8 membered heteroalkylene.
  • Embodiment 14 The composition ofembodiment 1, wherein Lofthe compound is independentlya 3 to 6 membered heteroalkylene.
  • Embodiment 15 The composition ofembodiment 1, wherein Lofthe compound is independently–NH-(substituted or unsubstituted (C 1 -C 4 )alkylene).
  • Embodiment 16 The composition ofembodiment 1, wherein Lofthe compound is independently–NH-(unsubstituted (C 1 -C 4 )alkylene).
  • composition ofembodiment 1 wherein Lofthe compound is independently–NHC(O)-(substituted or unsubstituted (C 1 -C 4 )alkylene).
  • Embodiment 18 The composition ofembodiment 1, wherein Lofthe compound is independently
  • Embodiment 19 The composition ofembodiment 1, wherein R 2 ofthe compound is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • Embodiment 20 The composition ofembodiment 1, wherein R 2 ofthe compound is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.
  • Embodiment 21 The composition ofembodiment 1, wherein R 2 ofthe compound is unsubstituted methyl.
  • Embodiment 22 The composition ofembodiment 1, wherein R 2 ofthe compound is H.
  • Embodiment 23 The composition ofembodiment 1, wherein R 3 ofthe compound is independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.
  • Embodiment 24 Embodiment 24.
  • composition ofembodiment 1, wherein R 3 ofthe compound is independentlysubstituted or unsubstituted (C 1 -C 10 )alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.
  • Embodiment 25 The composition ofembodiment 1, wherein R 3 ofthe compound is unsubstituted methyl.
  • Embodiment 26 The composition ofembodiment 1, wherein R 3 ofthe compound is H.
  • Embodiment 27 The composition ofembodiment 1, wherein R 2 and R 3 ofthe compound are joined to form a substituted or unsubstituted heterocycloalkyl.
  • Embodiment 28 Embodiment 28.
  • Embodiment 29 The composition ofembodiment 1, wherein R 2 and R 3 ofthe compound are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • Embodiment 30 The composition ofembodiment 1, wherein R 2 and R 3 ofthe compound are joined to form an unsubstituted 3 to 6 membered heterocycloalkyl.
  • Embodiment 31 The composition ofembodiment 1, wherein R 2 and R 3 ofthe
  • Embodiment 32 The composition ofembodiment 1, wherein n ofthe compound is 2.
  • Embodiment 33 The composition ofembodiment 1, wherein n ofthe compound is 1.
  • Embodiment 34 The composition ofembodiment 1, wherein R 1 ofthe compound is –NO 2 or–NH 2 .
  • Embodiment 35 The composition ofembodiment 34, wherein Lofthe compound is a bond.
  • Embodiment 36 The composition ofembodiment 1, the compound having the formula:
  • Embodiment 37 The composition ofembodiment 1 comprising a CDK4 inhibitor.
  • Embodiment 38 The composition ofembodiment 37 not comprising a CDK6 inhibitor.
  • Embodiment 39 The composition ofembodiment 1 comprising a CDK6 inhibitor.
  • Embodiment 40 The composition ofembodiment 39 not comprising a CDK4 inhibitor.
  • Embodiment 41 The composition ofone ofembodiments 1 to 40, further comprising a pharmaceuticallyacceptable excipient therebyforming a pharmaceutical composition.
  • Embodiment 42 Embodiment 42.
  • composition ofembodiment 41 wherein the compound is in a first dosage form and the CDK4 inhibitor or the CDK6 inhibitor is in a second dosage form.
  • Embodiment 43 The composition ofembodiment 41, wherein the pharmaceutical composition is a single dosage form.
  • Embodiment 44 A kit comprising a CDK4 inhibitor or a CDK6 inhibitor;and
  • heteroalkylene substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted
  • heteroarylene or a substituted or unsubstituted spirocyclic linker
  • R 2 is independentlya hydrogen, halogen, -CX b
  • R 3 is independentlya hydrogen, halogen, -CX c
  • R 2 and R 3 substituents mayoptionallybe joined to form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl;
  • R 4 is independentlya hydrogen, halogen, -CX d
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , and R 22 are independently hydrogen, halogen, -CX 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 Cl, -SO 3 H, - SO 4 H,
  • n is an integer from 0 to 5;
  • n 1 or 2;
  • n1, n2, n3, and n4 are independentlyan integer from 0 to 4;
  • X, X a , X b , X c and X d are independently–Cl, -Br, -I, or -F.
  • Embodiment 45 The kit ofembodiment 44, wherein the compound is in a first dosage form further comprising a pharmaceuticallyacceptable excipient and the CDK4 inhibitor or the CDK6 inhibitor is in a second dosage form further comprising a pharmaceutically acceptable excipient.
  • Embodiment 46 The kit ofembodiment 44, wherein the compound and the CDK4 inhibitor or the CDK6 inhibitor are within a dosage form further comprising a pharmaceutically acceptable excipient.
  • Embodiment 47 Embodiment 47.
  • Embodiment 48 A method oftreating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a composition of anyone ofembodiments 1 to 43 or the compound and the CDK4 inhibitor or CDK6 inhibitor of the kit ofone ofembodiments 44 to 50.
  • Embodiment 49 The method ofembodiment 48, wherein the hyperproliferative disorder is associated withestrogen receptor activity.
  • Embodiment 50 The method ofembodiment 48, wherein the hyperproliferative disorder is lymphangioleiomyomatosis.
  • Embodiment 51 The method ofembodiment 48, wherein the hyperproliferative disorder is a cancer.
  • Embodiment 52 The method ofembodiment 51, wherein the cancer is resistant to an anti-cancer agent.
  • Embodiment 53 The method ofembodiment 51, wherein the cancer is breast cancer, lung cancer, a gynecological cancer, ovarian cancer, endometrial cancer, or prostate cancer.
  • Embodiment 54 The method ofembodiment 51, wherein the cancer is a cancer of an estrogen target organ or tissue.
  • Embodiment 55 Embodiment 55.
  • a method ofinhibiting estrogen receptor activityin a subject in need thereof, comprising administering to the subject an effective amount of a composition of anyone ofembodiments 1 to 43 or the CDK4 inhibitor or CDK6 inhibitor ofthe kit ofone of embodiments 44 to 50.
  • Embodiment 56 The composition ofanyone ofembodiments 1-43, wherein the compound and the CDK4 inhibitor or the CDK6 inhibibor are present in the composition in a synergistic amount.
  • Embodiment 57 The kit ofanyone ofembodiments 44-47, wherein the compound and the CDK4 inhibitor or said CDK6 inhibibor are present in the kit in a synergistic amount.
  • Embodiment 58 The methods ofanyone ofembodiments 48-55, wherein the compound and the CDK4 inhibitor or the CDK6 inhibibor are present in the composition in a synergistic amount.
  • the phenolic hydroxyl group ofOHT binds to the same part ofthe ligand binding domain (LBD)as does the phenolic hydroxyl group ofE2 but, because ofthe hindered basic amino group in OHT(not present in E2), the waythe protein folds around the bound molecule is altered (helix12 folds in an unusual way)and the signal for DNA synthesis and cancer growthis inhibited.
  • LBD ligand binding domain
  • THF Tetrahydrofuran
  • DMF dimethylformamide
  • (8S,9S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl- 6,7,8,9,12,13,14,15,16,17-decahydro-11H-cyclopenta[a]phenanthren-11-one (11-ketone) was prepared using literature procedures.
  • the coupling constants are reported in Hertz (Hz) and the resonance patterns are reported withnotations as the following: br (broad), s (singlet), d (double), t (triplet), q (quartet)and m (multiplet).
  • High-resolution mass spectra were measured on a time-of-flight LC- MS.Thin-layer chromatography(TLC)was carried out using precoated silica gel sheets.Visual detection was performed withultraviolet light, p-anisaldehyde stain, potassium permanganate stain or iodine. Flash chromatography was performed using silica gel P60 (60 A, 40-63 ⁇ m) with compressed air.
  • Example 2.Compound Functional Characterization For the biological testing alternative code names for the compounds were used, namely JD101-JD160. The correspondence ofthe compound numbers in the design and synthesis and the code names for functional characterization are given in Table 1. Table 1: Correspondence of the Novel ER Antagonists Chemical names and their alternative Code Names for Functional Characterization.
  • Novel antiestrogen compounds can act as ER ⁇ downregulators.Fulvestrant (Faslodex R ) has been characterized as a selective ER ⁇ downregulator and a pure anti-estrogen. Fulvestrant inhibits the transcriptional response to estrogen stimulation and induces the degradation of estrogen receptor proteins (46,47). This drug has been demonstrated to be clinicallyeffective in treating metastatic breast cancer and represents an important option to extend the window of endocrine interventions before cytotoxic chemotherapybecomes the onlyother systemic treatment available for patients.
  • One problem withfulvestrant is that the drug requires intramuscular injection and maynot achieve optimal antitumor effects due to the limited doses that can be administered bythis drug deliverymethod.
  • MCF-7 breast cancer cells with high expression of ER ⁇ protein were treated with estradiol-17 ⁇ and either 1 ⁇ M or 10 ⁇ M concentrations of JD128 and JD140 for 48 hours.
  • FIG.3 shows results of W estern immunoblots of ER ⁇ protein levels after treatments.
  • Compound JD128 showed the greatest effect at suppressing estrogen receptor-alpha expression in MCF-7 breast cancer cells.As shown in FIG.3, estrogen receptor-alpha is down-regulated by antiestrogens.
  • MCF-7 breast cancer cells were estrogen-deprived for 48 hrs, then treated with1 nM estradiol-17 ⁇ (E2) or antiestrogens JD128 (128) or JD140 (140) at 1 ⁇ M or 10 ⁇ M
  • TAM-R cells To develop TAM-R cells, MCF-7 breast cells were cultivated invitro in the presence oftamoxifen as reported before (72).In brief, MCF-7 cell monolayers were cultivated in phenol-red-free RPMImedium containing 5% charcoal-stripped steroid-depleted (DCC)-fetal calfserum, antibiotics, glutamine (200 mM), and 4- hydroxytamoxifen (1 x10-7 M 4-OH-TAM).Cells were continuouslyexposed to this treatment for 12 months, during whichtime medium was replaced every4 days, and cell cultures were passaged bytrypsinization after 70% confluencywas reached. Initially, MCF-7 cell growthrates were reduced but, after 4 months’exposure to the medium, cell growthgraduallyincreased, indicating development ofa cell line resistant to the growth-inhibitoryproperties of4-OH-TAM.
  • DCC charcoal-stripped steroid-depleted
  • glutamine 200 mM
  • TAM-resistant This cell line, termed TAM-resistant, was cultured for a further 8 months in medium containing 4-OH-TAM before characterization studies. These cells were evaluated for expression ofEGFR, HER-2 and ER ⁇ -(FIG.2). The results show that TAM-resistant cells have higher levels ofHER-2 and EGFR as compared withtamoxifen-sensitive progenitor MCF-7 cells, while expression levels ofER remain essentiallyunchanged.This finding mayhave important implications for the design offuture therapeutic interventions.
  • FIG.4a-b. shows MCF-7 cells withacquired tamoxifen resistance show increased expression ofHER-1/EGFR and HER-2 receptors.
  • FIG.4a shows a W estern blot showing protein expression level ofHER2, EGFR, ER - and actin loading control in MCF-7 cells that were tamoxifen-sensitive (left)versus those that were tamoxifen- resistant (right).
  • FIG.4b shows levels ofHER-2, HER-1/EGFR and ER - receptors in MCF-7/TAM-R cells that were quantitated using established ELISA methods (73), withresults based on 3
  • MCF-7/TAM-R, MCF-7/ER- and parental cells MCF-7/CON (parental) cells are tamoxifen-sensitive, while MCF-7/TAM-R and MCF-7/ER- cells are known to be tamoxifen-resistant (11,14-16).
  • TAM-R (72)and MCF-7/ER- (16) cells are routinely cultured in RPMI1640 media with10% heat-inactivated FBS.For E2-free conditions, medium is changed 48 hbefore studies to phenol-red free RPMI1640 with1% dextran-coated, charcoal- treated (DCC) FBS.
  • MCF-7/CON cells express ER ⁇ but few HER2 receptors
  • MCF-7/TAM-R cells express bothER and HER2.
  • ER and HER2 were detected by established immunofluorescence microscopy methods with labeled antibodies to ER ⁇ and HER2 (14-16).
  • TAM-R cells also show increased expression ofHER2 byimmunofluorescence (72).
  • expression of ER ⁇ appears to be relatively stable among the several cell lines, withonlymodestlyless intensityofimmunofluorescence in TAM-R cells as compared to their paired controls.
  • [ 3 H]estradiol-17 - and varying concentrations (1 nM-10 ⁇ M)ofnew estrogen receptor downregulator (ERD)analogues The efficiencyofthe binding ofcompounds was measured by the loss ofradioactivityofthe [ 3 H]estradiol-17 -.A 100-fold molar excess ofunlabeled E2 was present with[3H]estradiol-17 - in paired samples for determination ofdisplaceable binding.ICI 182,780 (fulvestrant, 1 nM -10 -M)was used as a control.As shown in FIG.5, the ligand binding specificityoflabeled estradiol-17 - was suppressed effectivelyby10 ⁇ M ofERD compound S15 (JD105)compared to select test compounds.
  • FIG.5 shows specific binding of [ 3 H]estradiol-17 - byMCF-7 parental breast cancer cells is suppressed byour ERD compound S15 in this series ofanalogues (15).MCF-7 cells were incubated with2
  • Compounds S1-S14 show less activityin the assayabove than compound S15 (JD105)as shown in FIG.5.
  • Compounds S1-S14 are test compounds different from the exemplified compounds described herein.
  • ER down-regulation To determine ifselected compounds can down-regulate ER protein, we treated cells for 24-48 hrs in vitro withcandidate compounds at varying doses.Then, cells were disrupted and prepared for PAGE and W estern immunoblots using anti-ER ⁇ antibodies (see FIG.6).A representative experiment shows that a selected ERD at doses of>100 nM elicits reduced ER levels.Those ERDs withoptimal activityin down-regulating ER were investigated further in the chemistrylaboratoryto further refine and develop suchagents.
  • FIG.6 shows ERD S15 reduces ER protein levels in MCF-7 breast tumor cells.W estern immunoblot analysis ofER (66 kD)after treatment ofMCF-7 cells for 24 hours withSERM S15 at various concentrations (10, 100 and 1000 nM), ICI182,780 (ICI;fulvestrant;100 nM), tamoxifen (TM;100 nM)or control vehicle (CON).
  • ERD S15 inhibits phosphorylation ofMAPK, at both extracellular signal-regulated kinases ERK-1 (p44)and ERK-2 (p42).
  • ERD S15 was as effective as fulvestrant in inhibiting the rapid estrogen-induced MAPK phosphorylation in breast tumor cells invitro.
  • FIG.7 shows treatment ofMCF-7 parent cells with1 nM estradiol 17 - (E2) induces rapid phosphorylation ofMAPK (pMAPK).E2 but not vehicle (CN)induced rapid phosphorylation ofERK-1 (p44)and ERK-2 (p42).This activation was prevented when cells were pre-incubated with1000 nM ICI182,780 (ICI;Faslodex)or 1000 nM compound S15 in the presence ofestradiol (E2).
  • human non-small cell lung cancer cells A549 were grown in RPMI1640 medium with10% fetal bovine serum (FBS), then treated witheither 1 -M or 10 -M doses ofestrogen receptor antagonists JD128, JD140 or fulvestrant.Cell counts and viabilitytests (Trypan blue)were done every24 hours for 3 days.After 72 hours, proliferation was assessed using the CELLTITER 96 TM AQ ueous One Solution Cell Proliferation Assay(MTS)from Promega.Cell numbers were also assessed initiallybycell counts to confirm ELISA data.Eachantiestrogen was tested in at least in three independent experiments.
  • ER has a major role in controlling breast cancer growth.
  • Antiestrogen tamoxifen has been the most widelyused hormone therapy, achieving a 39% reduction in breast cancer recurrence and 31% reduction in mortalityin ER-positive earlybreast cancer.
  • Tamoxifen has important drawbacks: a limited period ofactivitybefore resistance develops;and undesirable side-effects in normal tissues suchas uterus due to the activityas a partial agonist.As long as ER is present, growthmaybe stimulated byestrogen, partial agonists or estrogen-independent action.Introduction ofaromatase inhibitors for postmenopausal patients, either initiallyor after tamoxifen, has yielded better outcomes than tamoxifen.However, in patients withadvanced breast cancer, onlyabout one third ofER-positive breast cancers respond to aromatase inhibitors, and resistance can evolve due to ER activation byER hypersensitivityor ligand-independent ER activ
  • fulvestrant is a pure ER antagonist withno major agonist activityand witha unique mechanism ofaction, i.e.downregulation ofER, due in part to induced destabilization and hyper-ubiquitination ofER leading to growthinhibition.But, fulvestrant suffers from low bioavailabilitywhichpresents a problem in the clinic.In about 14% of metastatic ER-positive breast cancers from patients withmultiple prior endocrine therapies, there is emerging evidence for the acquisition offunctionally-aberrant ESR1 withpoint mutations.
  • the human estrogen receptor-alpha is an ubiquitinated protein whose stabilityis affected differentiallyby agonists, antagonists, and selective estrogen receptor modulators.J.Biol.Chem.276, 35684– 356892.21.Robinson DR, W u YM, Vats P et al.(2013).Activating ESR1 mutations in hormone-resistant metastatic breast cancer.Nat Genet 2013, 45:1446-1451.
  • Example 5 Selective estrogen receptor downregulators and applications in ER- positive human cancers.
  • SERD compounds e.g., compounds disclosed herein, show that several of these agents are effective in blocking proliferation ofhuman NSCLC cells invitro (see FIG.S1 and Table S1 following).
  • DCC-FBS.Cell proliferation was measured using the MTS assay(Promega) as described in methods.Numbers represent the average of at least 3 experiments. NSCLC cells include A549, H1975 and H2122. The extra column on the right (MCF-7)is included to compare findings withthose on treatment of MCF-7 breast cancer cells; IC 50 ( ⁇ M) concentrations for inhibition ofcell proliferation after treatment withSERDs for 72 hrs in the presence of 1nM estradiol-17 ⁇ . MCF-7 cell proliferation was measured by
  • CDK 4/6 phosphorylates/ inactivates retinoblastoma (Rb)protein, whichallows the E2F-DP complexto encode proteins integral to DNA replication, therebycommitting the cell to cell cycle progression.
  • palbociclib PD0332991
  • CDK4/6 inhibitor a selective cyclin D kinase (CDK)4/6 inhibitor, is reported to preferentiallyinhibit proliferation ofluminal ER --positive breast cancer cell lines in vitro (19,20).As shown in FIG.S3, it is notable that CDK 4/6 partners withcyclin D
  • CDK 4/6 inhibitor palbociclib is currently FDA-approved for management ofadvanced ER --positive breast cancer in combination with letrozole or fulvestrant (19-22). Additional CDK 4/6 inhibitors are also being developed for management ofbreast and potentiallyother malignancies.

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Abstract

La présente invention concerne, entre autres, des compositions et des méthodes permettant de traiter ou de prévenir les désordres hyperprolifératifs, notamment le cancer.
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